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Hou Y, Fu Z, Wang C, Kucharzewska P, Guo Y, Zhang S. 27-Hydroxycholesterol in cancer development and drug resistance. J Enzyme Inhib Med Chem 2025; 40:2507670. [PMID: 40401382 PMCID: PMC12100970 DOI: 10.1080/14756366.2025.2507670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 04/25/2025] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
27-Hydroxycholesterol (27HC), a cholesterol metabolite, functions both as a selective oestrogen receptor (ER) modulator and a ligand for liver X receptors (LXRs). The discovery of 27HC involvement in carcinogenesis has unveiled new research avenues, yet its precise role remains controversial and context-dependent. In this review, we provide an overview of the biosynthesis and metabolism of 27HC and explore its cancer-associated signalling, with a particular focus on ER- and LXR-mediated pathways. Given the tissue-specific dual role of 27HC, we discuss its differential impact across various cancer types. Furthermore, we sort out 27HC-contributed drug resistance mechanisms from the perspectives of drug efflux, cellular proliferation, apoptosis, epithelial-mesenchymal transition (EMT), antioxidant defence, epigenetic modification, and metabolic reprogramming. Finally, we highlight the chemical inhibitors to mitigate 27HC-driven cancer progression and drug resistance. This review offers an updated role of 27HC in cancer biology, setting the stage for future research and the development of targeted therapeutics.
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Affiliation(s)
- Yaxin Hou
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Zhiguang Fu
- Department of Tumor Radiotherapy, Air Force Medical Center, People’s Liberation Army of China (PLA), Beijing, China
| | - Chenhui Wang
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Paulina Kucharzewska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, Warsaw, Poland
| | - Yuan Guo
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Sihe Zhang
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
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Contreras L, Rodríguez-Gil A, Muntané J, de la Cruz J. Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells. RNA Biol 2025; 22:1-11. [PMID: 40116042 PMCID: PMC11934173 DOI: 10.1080/15476286.2025.2483484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/04/2025] [Accepted: 03/17/2025] [Indexed: 03/23/2025] Open
Abstract
Sorafenib (Sfb) is a multikinase inhibitor regularly used for the management of patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned, which strongly correlates with the presence of established mRNA cis-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provides valuable information that can facilitate the analysis of other drugs for the development of novel combined treatment strategies based on Sfb therapy.
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Affiliation(s)
- Laura Contreras
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Alfonso Rodríguez-Gil
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
| | - Jordi Muntané
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Jesús de la Cruz
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
- Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Seville, Spain
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Wang J, Qiu K, Zhou S, Gan Y, Jiang K, Wang D, Wang H. Risk factors for hepatocellular carcinoma: an umbrella review of systematic review and meta-analysis. Ann Med 2025; 57:2455539. [PMID: 39834076 PMCID: PMC11753015 DOI: 10.1080/07853890.2025.2455539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength. METHODS This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria. RESULTS We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk. CONCLUSIONS HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.
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Affiliation(s)
- Jie Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Kaijie Qiu
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Songsheng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Yichao Gan
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Keting Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Donghuan Wang
- Operations Department, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Haibiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
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Darbà J, Ascanio M. Hepatocellular carcinoma: what are the differential costs compared to the general population? J Med Econ 2025; 28:471-478. [PMID: 40126406 DOI: 10.1080/13696998.2025.2484073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC), which accounts for about 90% of all primary liver cancer cases, is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. This study aims to analyse the differential costs of HCC-related hospital admissions compared to the general population in Spain. METHODS A retrospective multicenter study analyzed inpatient admissions from a Spanish national discharge database, covering 90% of hospitals between 2010 and 2022. HCC-related admissions were identified using ICD-9 and ICD-10 codes, while control admissions were selected from the general population in the same database without an HCC diagnosis. The direct hospitalization cost was included, covering medical examinations, procedures, medications, surgeries, personnel and equipment. Statistical methods, including nearest-neighbor matching, propensity score matching, and a generalized linear model, were used to estimate differential costs and to ensure comparability based on age, gender, and Charlson Comorbidity Index (CCI). RESULTS A total of 199,670 HCC-related hospital admissions and 200,000 control admissions were analyzed. Most HCC-related admissions involved male patients (78%) aged 66-85 years, with an average CCI of 5.18. HCC-related admissions incurred significantly higher costs, with an estimated differential cost of €1,303.68 using GLM, €1,804.25 via propensity score matching, and €1,767.77 using nearest-neighbor matching. Total costs per HCC admission ranged between €1,000 and €31,000. CONCLUSIONS HCC-related hospital admissions impose a significantly higher economic burden due to the complexity of care. Given the high mortality and resource utilization, advancements in early detection, treatment, and cost-effective interventions are needed to improve patient outcomes and reduce healthcare costs.
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Affiliation(s)
- Josep Darbà
- Department of Economics, Universitat de Barcelona, Barcelona, Spain
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Wang Q, Chen C, Zhao H, Jiao Y, Chen H, Wang P, Song T. Magnetotactic bacteria-mediated integrated magnetic targeted hyperthermia for in-situ deep-seated tumor. Colloids Surf B Biointerfaces 2025; 252:114658. [PMID: 40168695 DOI: 10.1016/j.colsurfb.2025.114658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/28/2025] [Accepted: 03/24/2025] [Indexed: 04/03/2025]
Abstract
Unlike hyperthermia after intratumoral injection, the method of integrated magnetic targeted hyperthermia (iMTH) guides magnetic medium to the target site and then directly performs in-situ heating, showing great potential for effective treatment of deep-seated tumors in the body. Magnetotactic bacteria (MTB), having chain-like arranged magnetic nanoparticles within its body and active movement along an external magnetic field, are considered as a very fitted material for iMTH. However, the amount of MTB concentrated on the deep-seated tumor posed a significant challenge for the successful implementation of iMTH. Herein, we aim to validate the strategy of integrating magnetic targeting and hyperthermia. An in-situ liver tumor model in mouse was developed as deep-seated tumors. After administering the polar MTB MO-1 intravenously via the tail vein, a focusing magnetic field navigated these bacteria to effectively accumulate at the deep-seated tumor site. Immediately afterwards, this targeted aggregation of MO-1 cells triggered a localized magnetic hyperthermia directly at the cancer site under an applied alternating magnetic field. Our findings demonstrated that this hyperthermia induced by the bacteria led to the death of liver cancer cells, thereby effectively curbing the progression and growth of the cancer. These promising results suggested that an iMTH approach was developed, harnessing the power of MTB. This method stands as an exciting and potential therapeutic strategy for the treatment of deep-seated tumors, offering new hope in the fight against cancer.
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Affiliation(s)
- Qingmeng Wang
- Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; International Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms, Beijing, China
| | - Changyou Chen
- Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; International Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms, Beijing, China.
| | - Haoyu Zhao
- Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; International Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms, Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yangkun Jiao
- Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; International Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms, Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Haitao Chen
- Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; International Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms, Beijing, China
| | - Pingping Wang
- Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; International Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms, Beijing, China
| | - Tao Song
- Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, China; International Laboratory of Evolution and Development of Magnetotactic Multicellular Organisms, Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Zheng B, Wang B, Sun W, Wang H, Yang C, Zeng M, Sheng R. MRI-based predictive model with obesity metabolic phenotype for postoperative survival in HBV-related hepatocellular carcinoma. Eur J Radiol 2025; 189:112201. [PMID: 40451092 DOI: 10.1016/j.ejrad.2025.112201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 05/13/2025] [Accepted: 05/26/2025] [Indexed: 06/11/2025]
Abstract
PURPOSE Obesity metabolic phenotypes may influence survival outcomes in hepatocellular carcinoma (HCC) patients. This study aimed to develop an MRI-based model for postoperative survival prediction in HBV-related HCC patients, focusing on obesity metabolic phenotypes. METHODS A retrospective cohort of 381 HBV-related HCC patients (312 males; mean age 55.9 ± 10.7 years) who underwent preoperative MRI and curative surgery was studied. Patients were categorized into three phenotypes: normal weight (NW), metabolically healthy overweight/obesity (MHOO) and metabolically unhealthy overweight/obesity (MUOO). Univariate and multivariate Cox regression analyses identified independent predictors of overall survival (OS). A predictive model was established and validated with cross-validation. RESULTS MHOO patients showed significantly better overall survival (OS) than NW patients (adjusted HR = 0.42, P = 0.030), while MUOO had no significant effect on OS (adjusted HR = 0.92, P = 0.779). Independent predictors included MHOO (HR = 0.44, P = 0.036), AST/ALT ratio > 1 (HR = 2.61, P = 0.001), tumor burden score > 5.0 (HR = 3.02, P < 0.001) and arterial rim enhancement (HR = 3.61, P < 0.001). The combined model achieved good performance in both training (C-index = 0.737) and validation (C-index = 0.715) sets. The predicted high-risk patients had worse OS than low-risk patients in the whole cohort (P < 0.001) and in patients at BCLC stage A (P < 0.001). The model outperformed the BCLC and CNLC staging systems in predictive efficacy (all P < 0.001) and clinical net benefit. CONCLUSIONS MHOO is protective for OS in HBV-related HCC. The MRI-based model integrating obesity metabolic phenotype, AST/ALT ratio, tumor burden score and arterial rim enhancement is valuable in survival prediction, offering superior prognostic stratification compared to current staging systems.
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Affiliation(s)
- Beixuan Zheng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China
| | - Bin Wang
- Department of Radiology, Zhongshan Wusong Hospital, Shanghai, 200940, PR China
| | - Wei Sun
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China
| | - Heqing Wang
- Department of Radiology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen 361015, PR China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China.
| | - Ruofan Sheng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China.
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Jiang X, Zhang Q, Zheng Z, Shen Z, Luo Q. Latent class analysis-derived classification for cancer-specific death stratification of hepatocellular carcinoma. Int J Cancer 2025; 157:325-335. [PMID: 40071657 DOI: 10.1002/ijc.35399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 02/15/2025] [Accepted: 02/24/2025] [Indexed: 05/16/2025]
Abstract
The heterogeneity in prognostic survival and treatment response of hepatocellular carcinoma (HCC) limits the accurate assessment of HCC-specific mortality. This study aimed to identify potential HCC subtypes through latent class analysis (LCA) to improve HCC-specific mortality prediction and optimize treatment recommendations. We analyzed data from 7746 HCC patients in the Surveillance, Epidemiology, and End Results (SEER) databases, incorporating demographic and clinicopathological information and applying LCA to identify HCC subtypes. Prognostic survival and treatment response across different HCC subtypes were evaluated utilizing Cox proportional hazards regression and competing risks models. The classification was externally validated with data from 6791 patients. Four HCC subtypes (LCAC1-LCAC4) were determined. Compared with LCAC1, both LCAC2 (HR = 1.887, p < .001) and LCAC4 (HR = 1.317, p < .001) were associated with significantly shorter overall survival. LCAC2 had the highest HCC-specific mortality (HR: 2.395, p < .001), followed by LCAC4 (HR: 1.531, p < .001), and LCAC3 (HR: 1.424, p < .001). LCAC3 was associated with the lowest risk of non-HCC-specific mortality (HR: 0.613, p < .001). Surgical treatment, particularly preoperative systemic therapy, significantly improved survival across all HCC subtypes, whereas chemotherapy and radiotherapy had limited efficacy in LCAC1 and LCAC3 patients. External validation corroborated these findings. This study provides a classification system that differentiates HCC-specific mortality, facilitating accurate survival stratification and treatment recommendations, and provides valuable insight for clinical decision-making.
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Affiliation(s)
- Xiaoyan Jiang
- Department of Gestational and Toxic Hepatopathy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Qianyuan Zhang
- Department of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China
| | - Ziying Zheng
- Department of Oncology Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, People's Republic of China
| | - Zhiyong Shen
- Department of Radiotherapy, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
- Department of Radiotherapy, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, Fujian, People's Republic of China
| | - Qiong Luo
- Department of Oncology Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China
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Ma C, Yu X, Zhang X, Su L, Jiang O, Cui R. Combination of radiotherapy and ICIs in advanced hepatocellular carcinoma: A systematic review of current evidence and future prospects (Review). Oncol Lett 2025; 30:342. [PMID: 40438865 PMCID: PMC12117537 DOI: 10.3892/ol.2025.15088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/24/2025] [Indexed: 06/01/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health concern because of its rising prevalence and high fatality rates. Conventional treatments for advanced HCC (aHCC) have limited success, emphasizing the need for novel treatment options. Radiotherapy (RT) treatments, such as stereotactic body radiation and proton therapy, improve local tumor management via precision targeting. Moreover, immune checkpoint inhibitors (ICIs) that target the programmed cell death protein 1(PD-1)/PD ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) pathways have promise for systemic antitumor effectiveness. The combination of RT and ICIs takes advantage of their complementary mechanisms: RT kills immunogenic cells and controls the tumor microenvironment to increase antigen presentation, whereas ICIs enhance and maintain antitumor immune responses. This combination enhances tumor regression and immune response in aHCC, improving response rate and progression-free survival with manageable safety. The present review aimed to summarize the rationale for combining RT + ICIs in patients with aHCC and clinical outcomes, as well as ways to enhance this combination technique. The combination of these models is a promising technique for improving outcomes for patients with aHCC and warrants further investigation.
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Affiliation(s)
- Cheng Ma
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Xinlin Yu
- Department of Oncology, The Affiliated Hospital of Chengdu University, Chengdu, Sichuan 610000, P.R. China
| | - Xialin Zhang
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Lihong Su
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Ou Jiang
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Ran Cui
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
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Chen T, Ye W, Gao S, Li Y, Luan J, Lv X, Wang S. Emerging importance of m6A modification in liver cancer and its potential therapeutic role. Biochim Biophys Acta Rev Cancer 2025; 1880:189299. [PMID: 40088993 DOI: 10.1016/j.bbcan.2025.189299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 03/04/2025] [Accepted: 03/09/2025] [Indexed: 03/17/2025]
Abstract
Liver cancer refers to malignant tumors that form in the liver and is usually divided into several types, the most common of which is hepatocellular carcinoma (HCC), which originates in liver cells. Other rare types of liver cancer include intrahepatic cholangiocarcinoma (iCCA). m6A modification is a chemical modification of RNA that usually manifests as the addition of a methyl group to adenine in the RNA molecule to form N6-methyladenosine. This modification exerts a critical role in various biological processes by regulating the metabolism of RNA, affecting gene expression. Recent studies have shown that m6A modification is closely related to the occurrence and development of liver cancer, and m6A regulators can further participate in the pathogenesis of liver cancer by regulating the expression of key genes and the function of specific cells. In this review, we provided an overview of the latest advances in m6A modification in liver cancer research and explored in detail the specific functions of different m6A regulators. Meanwhile, we deeply analyzed the mechanisms and roles of m6A modification in liver cancer, aiming to provide novel insights and references for the search for potential therapeutic targets. Finally, we discussed the prospects and challenges of targeting m6A regulators in liver cancer therapy.
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Affiliation(s)
- Tao Chen
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Wufei Ye
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Songsen Gao
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province 230022, China
| | - Yueran Li
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China
| | - Xiongwen Lv
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province 230032, China.
| | - Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province 241001, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province 230032, China.
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Wang Z, Li Y, Wang X, Zhang W, Chen Y, Lu X, Jin C, Tu L, Jiang T, Yang Y, Ma X, Zeng J, Wen Y, Efferth T. Precision Strike Strategy for Liver Diseases Trilogy with Xiao-Chai-Hu Decoction: A Meta-Analysis with Machine Learning. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156796. [PMID: 40347886 DOI: 10.1016/j.phymed.2025.156796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/30/2025] [Accepted: 04/20/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND AND PURPOSE The progression from hepatitis to liver fibrosis (LF) and ultimately to hepatic carcinoma (HCC) represents the advanced stages of various liver diseases. Currently, no universal treatment effectively addresses all three conditions. The Traditional Chinese Medicine formula Xiao-Chai-Hu decoction (XCHD) has shown promise in treating hepatitis, inhibiting LF, and serving as an adjunct therapy for HCC. This study evaluates the efficacy and optimal treatment durations of XCHD in managing these liver diseases using meta-analysis and machine learning techniques. METHODS Registered in the PROSPERO database (CRD42024534445), this meta-analysis systematically searched seven databases, including 54 studies with a total of 5,710 patients. Statistical analysis was performed using Stata 17.0. Five machine learning models-Random Forest (RF), XGBoost, Lasso, Multilayer Perceptron (MLP), and a stacking model combining these algorithms-were employed to analyze the data and predict the time-effect relationships. The optimal durations of XCHD treatment for the liver disease trilogy were subsequently projected. RESULTS XCHD significantly improved the primary outcome indicators for hepatitis, liver fibrosis, and HCC. Additionally, XCHD demonstrated a beneficial effect on liver dysfunction caused by these diseases. Machine learning predicted the optimal treatment durations of XCHD as 12 weeks for hepatitis, 20.31 weeks for liver fibrosis, and 12 weeks for HCC. CONCLUSION XCHD is effective in treating the liver disease trilogy, with optimal treatment durations of 12 weeks for hepatitis and HCC, and 20.31 weeks for liver fibrosis. These findings support the potential of XCHD in developing precise clinical strategies for managing liver diseases. This study innovatively integrates meta-analysis with machine learning to determine the optimal treatment durations, providing a novel approach for evidence-based precision medicine in Traditional Chinese Medicine.
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Affiliation(s)
- Zexin Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaobao Wang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaohua Lu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Chunmei Jin
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Lang Tu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Tao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiqin Yang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
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11
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Li W, Zhang J, Gao Y, Kong X, Sun X. Nervous system in hepatocellular carcinoma: Correlation, mechanisms, therapeutic implications, and future perspectives. Biochim Biophys Acta Rev Cancer 2025; 1880:189345. [PMID: 40355012 DOI: 10.1016/j.bbcan.2025.189345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous and complex cancer influenced by both the tumor microenvironment and multi-level regulation of the nervous system. Increasing evidence highlights critical roles of the central nervous system (CNS) and peripheral nervous system (PNS) in modulating HCC progression. Psychological stress and emotional disturbances, representing CNS dysregulation, directly accelerate tumor growth, metastasis, and impair anti-tumor immunity in HCC. PNS involvement, particularly autonomic innervation, extensively reshapes the hepatic tumor microenvironment. Specifically, sympathetic activation promotes immune suppression, tumor cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stemness via β-adrenergic signaling and hypoxia-inducible factor 1-alpha (HIF-1α) stabilization, whereas parasympathetic signals generally exert anti-inflammatory and tumor-suppressive effects mediated by acetylcholine. Neurotransmitters including epinephrine, norepinephrine, dopamine, serotonin, and acetylcholine precisely regulate critical pathways such as AKT/mTOR, ERK, and NF-κB, thereby driving malignant cell behaviors, immune evasion, and chemoresistance. Neuro-targeted pharmacological interventions (e.g., SSRIs, β-blockers, dopamine antagonists) and behavioral therapies have shown efficacy in preclinical studies, underscoring their therapeutic potential. Additionally, neural-associated biomarkers like NEDD9, CNTN1, and nerve growth factor (NGF) exhibit prognostic significance, supporting their future clinical application. By systematically integrating neuroscience with oncology, this review identifies innovative neural-based therapeutic strategies, highlights key mechanistic insights, and outlines promising directions for future research and personalized clinical management of HCC.
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Affiliation(s)
- Wenxuan Li
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China
| | - Jinghao Zhang
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China
| | - Yueqiu Gao
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
| | - Xuehua Sun
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
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12
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Liu M, Ke M, Lu H, Feng Z, Wang K, Wang D, Wang K, Bai Y, Yang S, Miao L, Chen Q, Sun M, Shan C, Hu J, Jiang L, Jin H, Hu J, Huang C, Wang R, Zhao W, Yu F. A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein. Bioorg Med Chem 2025; 124:118178. [PMID: 40186923 DOI: 10.1016/j.bmc.2025.118178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025]
Abstract
The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth in vitro and in vivo. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound 15a effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound 15a inhibited the proliferation and migration of HepG2 cells, and induced apoptosis in vitro. Furthermore, compound 15a significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound 15a enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.
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Affiliation(s)
- Mingyang Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Muyan Ke
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Hongchen Lu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Ziyu Feng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Kaixuan Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Danyang Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Kun Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Yueping Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China; Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China
| | - Song Yang
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China
| | - Lu Miao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Qiang Chen
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Mingming Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Changliang Shan
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China.
| | - Jiancheng Hu
- Cancer and Stem Cell Program, Duke-NUS Medical School, 8 College Road, 169857 Singapore, Singapore.
| | - Lingyu Jiang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Hongzhen Jin
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China
| | - Jinfang Hu
- State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Tiancheng Drug Assessment Co., Ltd, Tianjin 300193, Chinaa.
| | - Changjiang Huang
- State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Tiancheng Drug Assessment Co., Ltd, Tianjin 300193, Chinaa.
| | - Rui Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China.
| | - Wei Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China; Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China; Frontiers Science Center for New Organic Matter, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China.
| | - Fan Yu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China.
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13
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Wang L, Huan XJ, Song SS, Bao XB, Tian CQ, Miao ZH, Wang YQ. UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma. Biochem Pharmacol 2025; 237:116943. [PMID: 40228637 DOI: 10.1016/j.bcp.2025.116943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 03/18/2025] [Accepted: 04/11/2025] [Indexed: 04/16/2025]
Abstract
Ubiquitination factor E4B (UBE4B) is crucial to the high mortality rate and poor prognosis associated with hepatocellular carcinoma (HCC). Evidence suggests that aberrant epigenetic modifications significantly contribute to HCC carcinogenesis, making epigenetic mechanisms a promising area for therapeutic intervention. However, the precise role of UBE4B in the epigenetic dysregulation observed in HCC remains elusive. In this study, we silenced UBE4B in HCC cells and exposed them to a panel of epigenetic compounds. Notably, only bromodomain and extraterminal inhibitors (BETis) exhibited resistance to UBE4B silencing, while restoring UBE4B expression partially reversed this resistance. Furthermore, UBE4B deletion led to decreased growth rates and impaired proliferation, resulting in cell cycle arrest and diminished tumorigenicity. However, this deletion did not affect the cell cycle arrest induced by BETi. Interestingly, KLHL22, a ubiquitin substrate of UBE4B, accumulated in UBE4B-deleted cells. Knockdown of KLHL22 restored sensitivity to BETi, accompanied by downregulation of JAK2 and upregulation of its negative regulator, LNK. Additionally, UBE4B deletion resulted in decreased LNK expression, and LNK knockdown increased JAK2 expression and mediated resistance to BETi. Increased JAK2 subsequently targeted PIM1, further reducing the inhibitory effect of BETi. Directly silencing PIM1 in UBE4B-deleted cells restored BETi sensitivity. Overall, our findings provide novel insights into the relationship between UBE4B expression and BETi sensitivity, which is mediated through the KLHL22-JAK2-PIM1 regulatory axis. These findings not only deepen our understanding of the mechanisms underlying HCC progression but also suggest that targeting this axis may present a promising therapeutic strategy for enhancing the treatment outcomes of HCC.
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Affiliation(s)
- Li Wang
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Xia-Juan Huan
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
| | - Shan-Shan Song
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
| | - Xu-Bin Bao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
| | - Chang-Qing Tian
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China
| | - Ze-Hong Miao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Ying-Qing Wang
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
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14
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Schnabl SD, Klubien J, O'Rourke CJ, Bull Nordkild S, Kugler JM, Dam Nielsen S, Andersen JB, Pommergaard HC. Validation of Two Prognostic Gene Scores in Patients Undergoing Liver Resection for Hepatocellular Carcinoma. J Clin Exp Hepatol 2025; 15:102544. [PMID: 40248345 PMCID: PMC12002650 DOI: 10.1016/j.jceh.2025.102544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 03/04/2025] [Indexed: 04/19/2025] Open
Abstract
Background/Aims Several prognostic gene signatures have been proposed as predictors of the prognosis of hepatocellular carcinoma (HCC), yet none are implemented in the clinical setting. We aimed to validate two gene scores previously derived from European cohorts. Methods The patients who underwent liver resection for HCC at Copenhagen University Hospital, Rigshospitalet from 2014 to 2018 were included. RNA sequencing determined the expression of genes in the '5-gene score' (HN1, RAN, RAMP3, KRT19, TAF9B) and 'HepatoPredict' (CLU, DPT, SPRY2, CAPSN1). Univariable Cox regression assessed associations with overall and disease-free survival. These parameters were also analyzed in the The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) (n = 359) and National Institute of Health (NIH) (n = 178) cohorts. Results Among 51 patients (88% male), 59% had no underlying liver disease and 25% had cirrhosis. No individual genes were significantly associated with overall survival in the Danish cohort. In the TCGA-LIHC cohort, CLU was linked to better overall survival, and in the NIH cohort, high expression of SPRY2 was associated with poorer overall survival. In the TCGA-LIHC cohort, HN1, RAN, and TAF9B were associated with poorer overall survival, while RAMP3 was linked to better overall survival. No genes were associated with disease-free survival. Conclusion Few individual genes significantly predicted survival in the larger cohorts, and none in the Danish cohort. However, the clinical implication of this needs further investigation.
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Affiliation(s)
- Stinna D. Schnabl
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Jeanett Klubien
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Colm J. O'Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sophie Bull Nordkild
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Jan-Michael Kugler
- Institute for Molecular and Cellular Medicine, University of Copenhagen, Panum Institute, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Viro-immunology Research Unit, Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark
- Institute for Clinical Medicine, University of Copenhagen, Panum Institute, Copenhagen, Denmark
| | - Jesper B. Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hans-Christian Pommergaard
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
- Institute for Clinical Medicine, University of Copenhagen, Panum Institute, Copenhagen, Denmark
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15
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Xu K, Wu T, Li X, Zhang X, Liu X, Ma S, Dong W, Yang J, Liu Y, Fang W, Ju Y, Chen Y, Dai C, Gong Z, He W, Huang Z, Chang L, Ma W, Xia P, Chen X, Yuan Y. ADH1C maintains the homeostasis of metabolic microenvironment to inhibit steatotic hepatocellular carcinoma. Metabolism 2025; 168:156267. [PMID: 40233847 DOI: 10.1016/j.metabol.2025.156267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 04/17/2025]
Abstract
Steatotic hepatocellular carcinoma (HCC) has emerged as a significant subtype of HCC. Understanding the complex tumor microenvironment in HCC is particularly important for stratifying patients and improving treatment response. In this study, we performed proteomic analysis on clinical samples of steatotic HCC and identified human-specific gene alcohol dehydrogenase 1C (ADH1C) as a key factor. ADH1C is a favorable prognostic factor in both steatotic and non-steatotic HCC. ADH1C promotes fatty acid degradation through a novel non-enzymatic function, inhibiting the development of hepatocellular carcinoma. Specifically, in vitro experiments revealed that ADH1C interacts with splicing factor retinitis pigmentosa 9 (RP9) to enhance the splicing of key transcription factor peroxisome proliferator activated receptor alpha (PPARa) pre-mRNA, which is crucial for fatty acid degradation. The regulation of the ADH1C/RP9/PPARa axis was supported by in vivo experiments and clinical relevance. This leads to a reduction in the critical metabolite palmitic acid, subsequently decreasing the palmitoylation levels of oncogenic protein TEA domain transcription factor 1 (TEAD1), thereby regulating the hippo pathway and subsequent cell proliferation inhibition. Additionally, we found that ADH1C and PPARa can serve as combined biomarkers to distinguish between patients with steatotic and non-steatotic HCC. Combination therapy targeting ADH1C and anti-programmed cell death protein 1 (PD1) enhances the response of steatotic HCC to anti- PD1 immunotherapy. Our study revealed a central role of ADH1C/PPARa in lipid metabolism and HCC suppression. Targeting lipid metabolism via ADH1C/PPARa may provide new therapeutic strategies for the treatment of liver cancer.
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Affiliation(s)
- Kequan Xu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Tiangen Wu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Xiaomian Li
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Xiao Zhang
- Department of Liver Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Lane, Chengdu, Sichuan Province, PR China.
| | - Xinyu Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Shuxian Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Wenlong Dong
- University of Chinese Academy of Sciences, Beijing 100049, PR China.
| | - Jialing Yang
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
| | - Yingyi Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Weixian Fang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Yi Ju
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Yiran Chen
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 180 Fenglin Road, Shanghai 200032, PR China.
| | - Caixia Dai
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Zheng Gong
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
| | - Wenzhi He
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan 430072, PR China.
| | - Zan Huang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan 430072, PR China.
| | - Lei Chang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Weijie Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Peng Xia
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China; Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
| | - Xi Chen
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, PR China.
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16
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Lu Y, Xu MY, Lu L, Gu ZW, Yin AQ, Yin YF. Quality of care combined with mindfulness-based stress reduction intervention in patients undergoing arterial interventional embolization for liver tumors. World J Gastrointest Surg 2025; 17:105826. [DOI: 10.4240/wjgs.v17.i6.105826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/08/2025] [Accepted: 05/06/2025] [Indexed: 05/30/2025] Open
Abstract
BACKGROUND Although transarterial chemoembolization (TACE) is an effective treatment for liver cancer, clinical practice has shown that many patients experience significant psychological distress following the procedure, which can hinder postoperative recovery and prognosis. Therefore, effective and evidence-based interventions are urgently needed to address this issue.
AIM To evaluate the impact of nursing quality-sensitive indicators combined with mindfulness-based stress reduction (MBSR) interventions in patients undergoing TACE.
METHODS A total of 84 patients who underwent TACE from June 2022 to March 2024 were enrolled in the study. They were randomly assigned to either the observation group (n = 42), which received nursing quality-sensitive indicator-based care combined with MBSR intervention, or the control group (n = 42), which received routine care combined with MBSR intervention. Psychological stress response levels [assessed using the Trait Meta-Mood Scale (TMMS)], coping strategies [measured with the Jalowiec Coping Scale (JCS)], quality of care [evaluated using the Perceived Nursing Service Quality (PNSQ) scale], and overall patient satisfaction were compared between the two groups.
RESULTS After 4 weeks, the observation group demonstrated significantly higher TMMS scores, as well as increased optimism, support-seeking, bravery, PNSQ scores, and satisfaction (P < 0.05). In contrast, scores for self-dependence, conservatism, resignation, and avoidance in the JCS were significantly lower in the observation group than in the control group (P < 0.05).
CONCLUSION The combination of nursing quality-sensitive indicators and MBSR intervention in TACE patients not only reduces psychological stress and encourages a more positive attitude toward illness but also enhances nursing quality and improves the overall patient experience.
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Affiliation(s)
- Yi Lu
- Department of Catheter Room of Interventional, Taixing People's Hospital, Taixing 225400, Jiangsu Province, China
| | - Ming-Yang Xu
- Department of Neurology, Taixing People’s Hospital, Taixing 225400, Jiangsu Province, China
| | - Li Lu
- Department of Catheter Room of Interventional, Taixing People's Hospital, Taixing 225400, Jiangsu Province, China
| | - Zhi-Wei Gu
- Department of Catheter Room of Interventional, Taixing People's Hospital, Taixing 225400, Jiangsu Province, China
| | - Ai-Qin Yin
- Department of Catheter Room of Interventional, Taixing People's Hospital, Taixing 225400, Jiangsu Province, China
| | - Yin-Feng Yin
- Department of Outpatient, Taixing People’s Hospital, Taixing 225400, Jiangsu Province, China
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17
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Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
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Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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18
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Kong H, Chen X, Lee W, Xie X, Tao Y, Li M. Dual-color fluorescence detection of tumor-derived extracellular vesicles using a specific and serum-stable membrane-fusion approach. Biosens Bioelectron 2025; 278:117302. [PMID: 40101657 DOI: 10.1016/j.bios.2025.117302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/05/2025] [Accepted: 02/21/2025] [Indexed: 03/20/2025]
Abstract
Tumor-derived extracellular vesicles (tEVs), which are essential mediators for cell-to-cell communication during tumorigenesis and tumor development, have demonstrated significant diagnostic potential in cancer liquid biopsy, particularly through biomarkers like membrane proteins and inner microRNAs. However, traditional detection methods such as ELISA and qRT-PCR encounter challenges with low sensitivity and specificity, complex procedures, and high costs. Although emerging biosensors have been developed, these methods are limited to detecting a single type of tEV biomarker, which may result in misdiagnoses due to false-positive or false-negative signals. Herein, we introduce a specific and serum-stable membrane-fusion approach (SSMFA) capable of simultaneously detecting tEV proteins and microRNAs via dual-color fluorescence analysis. In this strategy, the established epithelial cell adhesion molecule (EpCAM) aptamer-modified serum-stable membrane-fusion liposome (AptSMFL) is labeled with fluorescence resonance energy transfer (FRET) dye pairs, which can specifically recognize EpCAM-overexpressed tEVs and induce serum-stable membrane fusion, allowing the quantification of EpCAM protein levels through red fluorescence changes resulting from FRET alterations. Meanwhile, SSMFA facilitates efficient transfection of the CRISPR/Cas13a probe into tEVs to analyze the levels of microRNA-21 (miR-21) in EpCAM-positive tEVs via green fluorescence detection. When tested on serum samples from hepatocellular carcinoma models, the SSMFA exhibited minimal sample volume requirement and rapid assay time (2 h) to effectively achieve accurate quantification of both tEV EpCAM protein and miR-21 levels. Additionally, this dual-biomarker detection method showed a strong correlation with tumor burden and significantly improved cancer diagnostic accuracy (AUC = 0.98), underscoring the potential of SSMFA as a promising tEV-based liquid biopsy assay for cancer diagnosis.
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Affiliation(s)
- Huimin Kong
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaodie Chen
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Weijen Lee
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Xi Xie
- State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou 510006, China.
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, China.
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China; Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, China.
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19
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Sajid MS, Varghese RS, Kroemer A, Ressom HW. Low-Abundance Serum Protein Biomarker Candidates for HCC in Patients with Liver Cirrhosis. J Proteome Res 2025. [PMID: 40490917 DOI: 10.1021/acs.jproteome.5c00231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, often presenting diagnostic challenges in patients with underlying liver cirrhosis (CIRR). In this study, we employed both untargeted and targeted analysis of low-abundance serum proteins to identify potential biomarkers for HCC. In the untargeted study, we identified 15 proteins that exhibited statistically significant differential expression in HCC vs CIRR. In the targeted study, we confirmed differential expression of retinol-binding protein 4 (RBP4), dermcidin (DCD), bone morphogenetic protein 1 (BMP1), and putative sodium-coupled neutral amino acid transporter 10 (SLC38A10) by parallel reaction monitoring (PRM). Receiver operating characteristic (ROC) analysis highlighted the diagnostic potential of these proteins, demonstrating superior performance compared to alpha-fetoprotein. Functional enrichment analysis via gene ontology (GO) and ingenuity pathway analysis (IPA) identified key pathways implicated in HCC pathogenesis, including the liver X receptor/retinoid X receptor (LXR/RXR) pathway, immune regulation, extracellular matrix remodeling, and oxidative stress responses. Network analysis underscored HSPA5 and PPARG as critical hubs mediating interactions among dysregulated proteins, linking these to tumor progression and metabolic dysfunction. These findings provide novel insights into the molecular mechanisms of HCC and identify RBP4, DCD, BMP1, and SLC38A10 as promising biomarkers for HCC in patients with liver cirrhosis.
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Affiliation(s)
- Muhammad Salman Sajid
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C. 20057, United States
| | - Rency S Varghese
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C. 20057, United States
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, D.C. 20057, United States
| | - Habtom W Ressom
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C. 20057, United States
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20
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Huang YB, Xu SM, Li M, Chen J, Lu CH, Liu QQ. Suppression of MRPL23 induces cellular senescence in hepatocellular carcinoma by targeting HMGB1. Discov Oncol 2025; 16:1041. [PMID: 40490666 DOI: 10.1007/s12672-025-02885-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Accepted: 06/02/2025] [Indexed: 06/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and remains a global health challenge. The biological process of HCC is very complex, involving the imbalance of tumor suppressor genes and oncogenes, abnormal activation of molecular signaling pathways, and the differentiation of HCC cells. Standard clinical approaches for HCC treatment encompass surgery, chemotherapy, and radiation therapy. However, treatment options for advanced HCC are constrained, primarily due to an incomplete understanding of its underlying mechanisms. Cellular senescence is a crucial mechanism that influences the pathophysiological processes of HCC and serves as a potent barrier to tumor development. Our research identified the biological functions and mechanisms of Mitochondrial Ribosomal Protein L23 (MRPL23) in relation to cellular senescence in HCC. Results demonstrated that MRPL23 was upregulated in both tumor tissues and hepatoma cells. Additionally, the inhibition of MRPL23 resulted in decreased cell proliferation and promoted cellular senescence. Moreover, MRPL23 deficiency protected against HCC progression in a mouse model. Finally, we confirmed that MRPL23 regulated cellular senescence by targeting HMGB1 using the inhibitor NecroX-7. These findings laid the foundation for developing potential therapies for HCC by inhibiting MRPL23 or inducing senescence.
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Affiliation(s)
- Ya-Bin Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Department of Gastroenterology, Rugao People's Hospital, Nantong, 226500, China
| | - Shi-Meng Xu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Min Li
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Jin Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Cui-Hua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
| | - Qing-Qing Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
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21
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Cui X, Ruan M, Li Y, Yang C, Zhang J, Jin R, Wu D, Sun W, Wang R. Characteristics and outcomes of primary and secondary resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol Immunother 2025; 74:239. [PMID: 40481877 PMCID: PMC12145340 DOI: 10.1007/s00262-025-04089-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Accepted: 05/12/2025] [Indexed: 06/11/2025]
Abstract
Resistance limits the efficacy and durability of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). Therefore, we conducted a retrospective cohort study to investigate the outcomes and characteristics of HCC patients with resistance to immunotherapy. Patients with HCC who have received ICIs at Eastern Hepatobiliary Surgery Hospital between 2016 and 2021 were retrospectively screened and divided into primary resistance, secondary resistance, and durable response group. Time to progression (TTP), overall survival (OS), subsequent management and post-progression survival (PPS) were analyzed. Of 496 patients included, 229 (46.2%) and 141 (28.4%) patients developed primary and secondary resistance, and 126 (25.4%) patients achieved a durable response, the median TTP was 2.83 [2.56-3.09] months, 11.93 [10.45-13.40] months, and not reached, respectively, whereas the median OS was 12.83 [10.36-15.30] months, 31.53 [28.09-34.97] and not reached, respectively. Multivariate logistic regression revealed that Child-Pugh score, BCLC stage, and combined systemic therapies (ICI plus bevacizumab or lenvatinib versus ICI monotherapy) were independently associated with primary resistance, and only combined systemic therapies (ICI plus bevacizumab versus ICI monotherapy) were independently associated with secondary resistance. AFP levels were independently associated with PPS in patients with primary resistance, while post-progression therapies (ICI-based therapies versus others) were independently associated with PPS in patients with resistance. The risk of resistance was notably lower in patients receiving the combination of ICI plus bevacizumab. High AFP levels were associated with the survival of patients with primary resistance. ICI-based maintenance therapy after resistance may provide a significant survival advantage for HCC patients.
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Affiliation(s)
- Xiaowen Cui
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Minghao Ruan
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Yao Li
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Cheng Yang
- Department of Special Treatment I and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, China
| | - Jin Zhang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Riming Jin
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Dong Wu
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Wen Sun
- National Center for Liver Cancer, The Naval Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
| | - Ruoyu Wang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, 225 Changhai Road, Shanghai, 200438, China.
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22
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Morita M, Tokumoto Y, Watanabe T, Imai Y, Yukimoto A, Shimamoto T, Yano R, Okazaki Y, Nakamura Y, Yoshida O, Miyake T, Hirooka M, Abe M, Hiasa Y. Endoplasmic reticulum stress sensor protein PERK in hepatic stellate cells promotes the progression of hepatocellular carcinoma via p38δ MAPK/IL-1β axis. Sci Rep 2025; 15:20030. [PMID: 40481076 PMCID: PMC12144300 DOI: 10.1038/s41598-025-04150-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 05/26/2025] [Indexed: 06/11/2025] Open
Abstract
Palmitic acid (PA) absorption from the intestine is increased in metabolic dysfunction-associated steatohepatitis (MASH). It induces endoplasmic reticulum (ER) stress and interleukin-1 beta (IL-1β) production in hepatic stellate cells (HSCs). Protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER stress sensor protein involved in HSC activation and liver fibrosis. However, its role in HSCs during hepatocellular carcinoma (HCC) progression remains unclear. This study clarified the process of IL-1β production via PERK in HSCs and explored the mechanism underlying MASH-related HCC progression. HSCs were treated with PA or transfected with PERK small-interfering RNA (siRNA) or PERK plasmid. Proliferation, scratch, and Transwell assays were performed on HCC cells cultured in the conditioned medium (CM) from HSCs. PA treatment increased PERK and IL-1β expression in HSCs. PERK knockdown decreased IL-1β expression, while its overexpression increased it in HSCs. The CM from PA-treated HSCs showed elevated IL-1β levels and enhanced HCC cells' proliferation, migration, and invasion; however, these effects were suppressed by PERK knockdown in HSCs. RNA-sequencing analysis revealed that p38δ mitogen-activated protein kinase (MAPK) is the intermediate molecule between PERK and IL-1β in HSCs. In the tumor microenvironment of MASH-related HCC, PERK in HSCs promotes HCC progression via the p38δ MAPK/IL-1β axis.
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Affiliation(s)
- Makoto Morita
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yusuke Imai
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Atsushi Yukimoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Toyoki Shimamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Ryo Yano
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yuki Okazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoshiko Nakamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
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23
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Xu X, Cheng Y, Yang Z, Yin Y, Qian Y, Yang H, Zhu S, Tian H, Zhuang Y, Zhu S, Yang P, Qin S, Shen W. Wogonin potentiates the irradiation effect on hepatocellular carcinoma by activating the Hippo-Yes-associated protein/transcriptional co-activator with PDZ-binding motif pathway. Int Immunopharmacol 2025; 157:114740. [PMID: 40318272 DOI: 10.1016/j.intimp.2025.114740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 04/11/2025] [Accepted: 04/23/2025] [Indexed: 05/07/2025]
Abstract
OBJECTIVE To investigate whether wogonin increases the radiosensitivity of hepatocellular carcinoma (HCC) cells by activating Hippo-Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling. METHODS HCC cells were treated with irradiation and wogonin; their proliferation and apoptosis were evaluated. Xenograft models were established to assess the radio-synergistic effects of wogonin; we evaluated whether wogonin influences the efficacy of radiotherapy in HCC cells by activating Hippo-YAP/TAZ signaling. RESULTS Fifty micromolar wogonin enhanced the radiosensitivity of HCC cells; 4-Gy X-rays promoted apoptosis in HCC cells. Wogonin pretreatment significantly increased radiosensitivity. In xenograft models, tumor weight and volume in the 100 mg/kg wogonin plus irradiation group were significantly reduced; pYAP and pTAZ levels were downregulated in HCC cells treated with radiotherapy. Following treatment with 4-Gy X-rays and 100 μM wogonin, the relative pYAP/total YAP and pTAZ/total TAZ ratios increased. We identified the possible target genes of YAP/TAZ: AXL, CCN1, and CCN2. WB results revealed the upregulation of AXL, CCN1, and CCN2 in the irradiation group. However, in the group receiving irradiation and wogonin, the protein expression levels of AXL, CCN1, and CCN2 were downregulated. XMU-MP-1 inhibited pYAP and pTAZ expression in the combination treatment group, thereby promoting AXL, CCN1, and CCN2 expression. The proliferative ability of HCC cells in the wogonin plus irradiation group was partially recovered following treatment with XMU-MP-1. Apoptosis in HCC cells was reversed after pretreatment with 2 μM XMU-MP-1 in the wogonin plus irradiation group. CONCLUSION Wogonin may modulate Hippo-YAP/TAZ signaling and enhance the radiosensitivity of HCCs.
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Affiliation(s)
- Xiao Xu
- Department of Radiotherapy, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China; Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Yan Cheng
- School of Computer Science and Engineering, Taizhou Institute of Science & Technology, Taizhou 225300, Jiangsu, China
| | - Zeyu Yang
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou 215006, Jiangsu, China
| | - Yong Yin
- Department of Science and Technology, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Yonghong Qian
- Department of Radiotherapy, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Haiyu Yang
- Department of Clinical Laboratory, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Shusheng Zhu
- Department of Thoracic Surgery, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Hu Tian
- Department of Science and Technology, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Yanshuang Zhuang
- Department of Science and Technology, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Shimin Zhu
- Department of Radiotherapy, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Pingjin Yang
- Department of Clinical Laboratory, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Songbing Qin
- Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
| | - Weigan Shen
- Department of Cell Biology, Yangzhou University Medical College, Yangzhou 225100, Jiangsu, China.
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24
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Li YF, Yao LQ, Li C, Ren H, Gong JB, Wu H, Gu LH, Liang YJ, Yang YZ, Lin KY, Li ZQ, Zheng QX, Chen TH, Zhou YH, Wang H, Guo HW, Xu JH, Chen Z, Shen F, Wang MD, Yang T. Statistical Cure After Hepatectomy for Hepatitis B Virus-Associated Hepatocellular Carcinoma: A Risk-Stratification Model. Ann Surg Oncol 2025; 32:4396-4407. [PMID: 40188279 DOI: 10.1245/s10434-025-17176-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 02/27/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Statistical cure, defined as achieving life expectancy comparable with that of disease-free individuals, has not been specifically investigated in hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC), which accounts for more than 50% of the global HCC burden. This study aimed to develop a cure model for HBV-HCC after hepatectomy using matched HBV carriers and the general population as reference groups. METHODS From a Chinese multicenter database, HBV-HCC patients who underwent curative-intent hepatectomy were retrospectively reviewed. Independent prognostic factors were identified through Cox regression. A spline-based cure model was applied using two reference populations: matched Chinese HBV carriers (from Shanghai Center for Disease Control and Prevention) and the general population (from the National Bureau of Statistics). RESULTS The study analyzed 740 HBV-HCC patients. The following eight independent risk factors were identified: preoperative high viral load (hazard ratio [HR] 1.27), Child-Pugh grade (HR 1.21 and 1.43), multiple tumors (HR 1.70), tumor size greater than 5.0 cm (HR 1.47), macrovascular invasion (HR 3.33), microvascular invasion (HR 1.25), intraoperative blood transfusion (HR 1.21), and postoperative HBV reactivation (HR 1.89). The overall cure probability was 21.2% versus that for HBV carriers and 11.1% versus that for the general population. Risk stratification identified distinct groups relative to HBV carriers. Low risk (64.2%) showed an initial cure rate of 30.3% and achieved a 95% cure probability by 8.6 years, whereas high risk (10.5%) showed negligible cure probability. CONCLUSIONS This first HBV-HCC-specific cure model demonstrated that statistical cure is achievable for a subset of patients after hepatectomy. Risk stratification identifies patients with varying cure probabilities, providing valuable guidance for personalized treatment strategies and surveillance protocols.
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Affiliation(s)
- Yi-Fan Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hong Ren
- Department of Viral Hepatitis Control and Prevention, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Jin-Bo Gong
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ying-Jian Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yu-Ze Yang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Kong-Ying Lin
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Zi-Qiang Li
- Department of Liver Transplantation and Hepatic Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Qi-Xuan Zheng
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Ziyang, China
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Pu'er, China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Liuyang, China
| | - Hong-Wei Guo
- The 2nd Department of General Surgery, The Second People's Hospital of Changzhi, Changzhi, China
| | - Jia-Hao Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
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25
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Ben Khaled N, Zarka V, Hobeika B, Schneider J, Rau M, Weich A, Leicht HB, Ye L, Piseddu I, Dill MT, Kandulski A, Pinter M, Ehmer U, Schirmacher P, Marquardt JU, Mayerle J, De Toni EN, Geier A, Reiter FP. Therapeutic Sequences of Systemic Therapy After Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma: Real-World Analysis of the IMMUreal Cohort. Aliment Pharmacol Ther 2025; 61:1755-1766. [PMID: 40181694 PMCID: PMC12074566 DOI: 10.1111/apt.70090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/25/2024] [Accepted: 03/09/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND The introduction of several new systemic therapies in recent years has significantly altered the treatment landscape for advanced hepatocellular carcinoma. However, while the approval of the combination of atezolizumab and bevacizumab as the preferred first-line therapy over sorafenib represents progress, it has also raised uncertainties regarding optimal treatment sequencing for advanced disease. AIMS This study evaluates the sequential treatment of hepatocellular carcinoma following therapy with atezolizumab and bevacizumab, providing evidence from a prospective real-world cohort. METHODS Data were derived from the ongoing IMMUreal cohort, which investigates immunotherapy in hepatocellular carcinoma across two tertiary centres in Bavaria. A total of 124 patients treated with atezolizumab and bevacizumab as first-line therapy between June 2020 and December 2023 were analysed. Feasibility, treatment patterns, and outcomes of sequential therapy were assessed, with a focus on defined prognostic subgroups. RESULTS The median overall survival under real-world conditions was 19.8 months. Less than half of the patients (41.2%) proceeded to second-line therapy, and only 19.2% were eligible for third-line treatment. This decline in treatment eligibility corresponded to a marked reduction in therapy duration and progressive deterioration in liver function, as indicated by Albumin-Bilirubin and Child-Pugh scores. While patients with worse baseline liver function, such as patients with Child-Pugh B or ALBI > 1, had a significantly lower probability of transitioning to 2nd line therapy, no significant association was found between the number of treatment lines and factors such as liver cirrhosis, poor physical condition, extrahepatic disease, or macrovascular invasion. CONCLUSIONS Sequential therapy following atezolizumab and bevacizumab is feasible only for selected patients. However, preserving liver function seems crucial to optimising multi-line therapy and improving outcomes in advanced hepatocellular carcinoma.
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Affiliation(s)
- Najib Ben Khaled
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Valentina Zarka
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Bernard Hobeika
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Julia Schneider
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Monika Rau
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Alexander Weich
- Division of Gastroenterology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Hans Benno Leicht
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Liangtao Ye
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
- Digestive Diseases CenterThe Seventh Affiliated Hospital, Sun Yat‐Sen UniversityShenzhenChina
| | - Ignazio Piseddu
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Michael T. Dill
- Department of Gastroenterology, Infectious Diseases and IntoxicationHeidelberg University HospitalHeidelbergGermany
- National Center for Tumor Diseases (NCT)NCT Heidelberg, a Partnership Between DKFZ and Heidelberg University HospitalHeidelbergGermany
- German Cancer Research Center (DKFZ) HeidelbergResearch Group Experimental Hepatology, Inflammation and CancerHeidelbergGermany
| | - Arne Kandulski
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine IUniversity Hospital RegensburgRegensburgGermany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Ursula Ehmer
- Clinical Department for Internal Medicine II, Department of Clinical Medicine, TUM School of Medicine and Health, University Medical Center, Technical University of MunichMunichGermany
| | | | | | - Julia Mayerle
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Enrico N. De Toni
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Andreas Geier
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Florian P. Reiter
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
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26
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Han Y, Kong W, Shang Q, Liu Y, Ni X, Yang L, Lei J. Discovery of targeting USP10-mediated proline metabolism arrangement to inhibit hepatocellular carcinoma progression. Biochem Pharmacol 2025; 236:116904. [PMID: 40158816 DOI: 10.1016/j.bcp.2025.116904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 03/08/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025]
Abstract
Metabolic dysregulation is closely related to hepatocellular carcinoma (HCC) progression. Aberrant proline metabolism plays crucial roles in HCC onset and development. However, the detailed molecular mechanisms of proline metabolism in HCC remain unclear. In this study, we reported that hydroxyproline, a metabolite of proline, is a key causal factor of HCC progression using Mendelian randomization analysis. An elevated level of hydroxyproline promotes HCC cell growth, migration, and invasion. Using a non-targeted metabolomics approach, we found that USP10 increases the amount of proline and hydroxyproline in HCC cells. We subsequently proved that USP10 stabilizes Yes-associated protein 1 (YAP1), enhancing YAP1/TEA domain transcription factor 4 (TEAD4)-mediated transcription of prolyl 4-hydroxylase subunit alpha 1 (P4HA1). This leads to increased expression of P4HA1, which alters the proline catabolic profile. In contrast, knocking down USP10 or suppressing its activity reduced the expression of P4HA1. Given the crucial roles of USP10 in HCC progression, we further validated ginkgolic acid, a hit compound that targets USP10, leading to potential anti-HCC efficacy in xenograft mouse models. Overall, our study provides novel insights into the role and potential molecular mechanisms of USP10 on proline metabolism in HCC for the first time, as well as offers a promising therapeutic strategy of targeting USP10 for HCC treatment.
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Affiliation(s)
- Yinze Han
- National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Weili Kong
- National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qixin Shang
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuanzhi Liu
- National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xincheng Ni
- National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lin Yang
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jian Lei
- National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Wang Q, Sun L, Zhang G, Chen Z, Li G, Jin R. A novel nomogram based on machine learning predicting overall survival for hepatocellular carcinoma patients with dynamic α‑fetoprotein level changes after local resection. Oncol Lett 2025; 29:310. [PMID: 40342725 PMCID: PMC12059617 DOI: 10.3892/ol.2025.15056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 03/20/2025] [Indexed: 05/11/2025] Open
Abstract
The principal aim of the present study was to develop and validate a nomogram predicting overall survival (OS) in patients with α-fetoprotein (AFP)-negative hepatocellular carcinoma (AFP-NHCC) who experience dynamic changes in AFP level after hepatectomy. A cohort of 870 patients were enrolled and randomly assigned into a training cohort (n=600) and a validation cohort (n=270) at a 7:3 ratio. The key variables contributing to the nomogram were determined through random survival forest analysis and multivariate Cox regression. The discriminative ability of the nomogram was evaluated using time-dependent receiver operating characteristic curves and the area under the curves. Furthermore, the nomogram was comprehensively assessed using the concordance index (C-index), calibration curves and clinical decision curve analysis (DCA). Kaplan-Meier (KM) curves analysis was employed to discern survival rates across diverse risk strata of patients. Ultimately, the nomogram incorporated critical factors including sex, tumor size, globulin levels, gamma-glutamyl transferase and fibrinogen levels. In the training and validation cohorts, the C-indexes were 0.72 [95% confidence interval (CI): 0.685-0.755) and 0.664 (95% CI: 0.611-0.717], respectively, attesting to its predictive validity. The nomogram demonstrated excellent calibration and DCA further confirmed its clinical usefulness. Additionally, KM curve analysis unveiled statistically significant differences in OS among three distinct risk groups. In conclusion, the present study successfully formulated a nomogram predicting 3-, 5- and 8-year OS in patients with AFP-NHCC with dynamic changes in AFP level post-local resection. This model serves as a valuable tool for clinicians to promptly identify high-risk patients, thereby facilitating timely interventions and potentially enhancing patient survival outcomes.
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Affiliation(s)
- Qi Wang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
- Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Lina Sun
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
- Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Gongming Zhang
- Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Zhuangzhuang Chen
- Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Guangming Li
- Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Ronghua Jin
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
- Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
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Oura K, Morishita A, Yano R, Manabe T, Takuma K, Nakahara M, Tadokoro T, Fujita K, Mimura S, Tani J, Tatsuta M, Himoto T, Masaki T, Kobara H. Circulating miR-485-3p as a biomarker for VEGF-associated therapeutic response to atezolizumab plus bevacizumab in hepatocellular carcinoma. J Gastroenterol 2025; 60:770-782. [PMID: 40180668 DOI: 10.1007/s00535-025-02239-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/25/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND In atezolizumab/bevacizumab (atezo/bev) therapy for unresectable hepatocellular carcinoma (HCC), the tumor immune environment is regulated through vascular endothelial growth factor A (VEGFA) inhibition to maximize immune checkpoint blockade; however, evidence for VEGFA as a biomarker is limited. This study aimed to investigate serum VEGFA and associated microRNAs (miRNAs) as rapid biomarkers and their regulatory mechanisms in the microenvironment of HCC. METHODS Fifty-four patients with unresectable HCC who were treated with atezo/bev therapy were enrolled and assigned into objective response (OR) and non-OR groups according to the best therapeutic response in 12 weeks using the modified response evaluation criteria in solid tumors. Serum VEGFA levels and associated miRNA expression were compared. Furthermore, the effect of cell transfection with specific miRNA was investigated. RESULT There was no significant difference in the pre-treatment serum VEGFA levels between the groups; however, the 3-week/pre-treatment ratio of serum VEGFA levels was significantly lower in the OR group than in the non-OR group. The pre-treatment serum levels of 10 miRNAs, especially miR-485-3p involved in VEGFA expression, were higher in the OR group than in the non-OR group and were further elevated after 1-7 days and 3 weeks. MiR-485-3p suppressed HuH-7 migration, enhanced the expression of protein inhibitor of activated (PIA) signal transducer and activator of transcription 3 (STAT3) (PIAS3), and suppressed the expression of phosphorylated STAT3/VEGFA. CONCLUSION Circulating miR-485-3p is a more sensitive biomarker than VEGFA for the early prediction of therapeutic response in atezo/bev therapy for HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan.
| | - Rie Yano
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Takushi Manabe
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Miwa Tatsuta
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
- Department of Gastroenterology, KKR Takamatsu Hospital, Takamatsu, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
- Department of Gastroenterology, Kagawa Saiseikai Hospital, Takamatsu, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
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Chen JH, Lu L, Zhang XY, Xiang BD, Xu X, Li XC, Huang ZY, Wen TF, Luo LP, Huang J, Zhong JH, Liu ZK, Li CX, Long X, Zhu WW, Yang X, Wang CQ, Jia HL, Zhang JB, Zeng YY, Lu CD, Qin LX. Adjuvant lenvatinib in combination with transarterial chemoembolization for hepatocellular carcinoma patients with high risk of postoperative recurrence: A multicenter prospective cohort study. Hepatobiliary Pancreat Dis Int 2025; 24:277-285. [PMID: 40187927 DOI: 10.1016/j.hbpd.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 01/24/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND The high recurrent rate after surgery hinders the survival of patients with hepatocellular carcinoma (HCC). This prospective cohort study aimed to evaluate the efficacy and safety of lenvatinib plus transarterial chemoembolization (TACE) as an adjuvant therapy in HCC patients with high risk of recurrence. METHODS Patients were enrolled from eight hepatobiliary centers in China. The primary endpoint was disease-free survival (DFS). The secondary endpoints were overall survival (OS) and safety. Additionally, propensity score matching (PSM) and other three propensity score analyses were performed to balance the potential baseline bias to validate the conclusion. The adverse events (AEs) were recorded throughout the study. The study was registered at ClinicalTrials.gov (NCT03838796). RESULTS A total of 297 patients were enrolled, with 147 in the LEN + TACE group and 150 in the TACE group. Before PSM, the LEN + TACE group achieved significantly better DFS than the TACE group (19.0 vs. 10.0 months, P = 0.011). PSM analysis identified 111 matched pairs. After PSM, the LEN + TACE group also showed better DFS (19.0 vs. 9.0 months, P = 0.018). Other three propensity score analyses yielded similar DFS benefit tendency. Furthermore, favorable OS was also obtained in the LEN + TACE group before PSM. Lenvatinib related AEs of grade 3 or 4 occurred in 28.6% of the patients in the LEN + TACE group. CONCLUSIONS Adjuvant lenvatinib plus TACE might be a promising adjuvant approach for HCC patients with high risk of recurrence, which could significantly prolong DFS and potentially OS with a manageable safety profile.
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Affiliation(s)
- Jin-Hong Chen
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Lu Lu
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Xiao-Yun Zhang
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Bang-De Xiang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning 537406, China
| | - Xiao Xu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xiang-Cheng Li
- Hepatobiliary Center, the First Affiliated Hospital, Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China
| | - Zhi-Yong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tian-Fu Wen
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liu-Ping Luo
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou 350025, China
| | - Jing Huang
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo 315048, China
| | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning 537406, China
| | - Zhi-Kun Liu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China; Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China
| | - Chang-Xian Li
- Hepatobiliary Center, the First Affiliated Hospital, Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China
| | - Xin Long
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wen-Wei Zhu
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Xin Yang
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Chao-Qun Wang
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Hu-Liang Jia
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Ju-Bo Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou 350025, China.
| | - Cai-De Lu
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo 315048, China.
| | - Lun-Xiu Qin
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
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Jiang H, Li B, Zheng T, Qin Y, Wu Y, Wu Z, Ronot M, Chernyak V, Fowler KJ, Bashir MR, Chen W, Wang YC, Ju S, Song B. MRI-based prediction of microvascular invasion/high tumor grade and adjuvant therapy benefit for solitary HCC ≤ 5 cm: a multicenter cohort study. Eur Radiol 2025; 35:3223-3237. [PMID: 39702639 PMCID: PMC12081510 DOI: 10.1007/s00330-024-11295-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/25/2024] [Accepted: 11/16/2024] [Indexed: 12/21/2024]
Abstract
OBJECTIVES To develop and externally validate an MRI-based diagnostic model for microvascular invasion (MVI) or Edmondson-Steiner G3/4 (i.e., high-risk histopathology) in solitary BCLC 0/A hepatocellular carcinoma (HCC) ≤ 5 cm and to assess its performance in predicting adjuvant therapy benefits. MATERIALS AND METHODS This multicenter retrospective cohort study included 577 consecutive adult patients who underwent contrast-enhanced MRI and subsequent curative resection or ablation for solitary BCLC 0/A HCC ≤ 5 cm (December 2011 to January 2024) from four hospitals. For resection-treated patients, a diagnostic model integrating clinical and 50 semantic MRI features was developed against pathology with logistic regression analyses on the training set (center 1) and externally validated on the testing dataset (centers 2-4), with its utilities in predicting posttreatment recurrence-free survival (RFS) and adjuvant therapy benefit evaluated by Cox regression analyses. RESULTS Serum α-fetoprotein > 100 ng/mL (odds ratio (OR), 1.94; p = 0.006), non-simple nodular growth subtype (OR, 1.69; p = 0.03), and the VICT2 trait (OR, 4.49; p < 0.001) were included in the MVI or high-grade (MHG) trait, with testing set AUC, sensitivity, and specificity of 0.832, 74.0%, and 82.5%, respectively. In the multivariable Cox analysis, the MHG-positive status was associated with worse RFS (resection testing set HR, 3.55, p = 0.02; ablation HR, 3.45, p < 0.001), and adjuvant therapy was associated with improved RFS only for the MHG-positive patients (resection HR, 0.39, p < 0.001; ablation HR, 0.30, p = 0.005). CONCLUSION The MHG trait effectively predicted high-risk histopathology, RFS and adjuvant therapy benefit among patients receiving curative resection or ablation for solitary BCLC 0/A HCC ≤ 5 cm. KEY POINTS Question Despite being associated with increased recurrence and potential benefit from adjuvancy in HCC, microvascular invasion or Edmondson-Steiner grade 3/4 are hardly assessable noninvasively. Findings We developed and externally validated an MRI-based model for predicting high-risk histopathology, post-resection/ablation recurrence-free survival, and adjuvant therapy benefit in solitary HCC ≤ 5 cm. Clinical relevance Among patients receiving curative-intent resection or ablation for solitary HCC ≤ 5 cm, noninvasive identification of high-risk histopathology (MVI or high-grade) using our proposed MRI model may help improve individualized prognostication and patient selection for adjuvant therapies.
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Affiliation(s)
- Hanyu Jiang
- Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Binrong Li
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Tianying Zheng
- Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yun Qin
- Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuanan Wu
- Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhenru Wu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Maxime Ronot
- Université Paris Cité, UMR 1149, CRI, Paris & Service de Radiologie, Hôpital Beaujon, APHP.Nord, Clichy, France
| | - Victoria Chernyak
- Department of Radiology, Memorial Sloan Kettering Cancer Center, NYC, New York, NY, USA
| | - Kathryn J Fowler
- Department of Radiology, University of California San Diego, San Diego, CA, USA
| | - Mustafa R Bashir
- Department of Radiology, Center for Advanced Magnetic Resonance in Medicine, and Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Weixia Chen
- Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuan-Cheng Wang
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
| | - Shenghong Ju
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
| | - Bin Song
- Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Department of Radiology, Sanya People's Hospital, Sanya, Hainan, China.
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Park E, Subasi NB, Wang X, Kmeid M, Chen A, Tooke-Barry C, Lee H. CXCR2 expression is associated with prostate-specific membrane antigen expression in hepatocellular carcinoma: reappraisal of tumor microenvironment and angiogenesis. Clin Transl Oncol 2025; 27:2544-2556. [PMID: 39636498 DOI: 10.1007/s12094-024-03789-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024]
Abstract
PURPOSE Angiogenesis is a critical component of neoplastic progression, and inflammatory cells within the tumor microenvironment contribute to neoangiogenesis. Prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of various solid tumors, including hepatocellular carcinoma (HCC). Also, CXCR2 + inflammatory cells, including CD15 + neutrophils, play crucial roles in HCC progression. We evaluated the associations between PSMA expression and CXCR2 + inflammatory cells in HCC by immunohistochemistry (IHC). METHODS CXCR2 expression and its correlation with PSMA, the PSMA/CD34 ratio, immune markers (CD3, CD15, CD68, and CD163), clinical parameters, and oncologic outcomes were evaluated in 76 HCC and background benign liver tissue. RESULTS PSMA and the PSMA/CD34 ratio showed a positive correlation with intratumoral CXCR2, but not with intratumoral CD15. Intratumoral CXCR2 + cell count was positively associated with intratumoral CD3, CD15, CD68, and CD163 expression levels. In the benign compartment, CXCR2 was significantly associated with CD15. Metabolic dysfunction-associated steatotic liver disease (MASLD) risk factors and cirrhosis had an opposite effect on CXCR2 + cell count in benign liver tissue. Higher CD15 + cell count in the benign liver was associated with decreased overall survival (OS) and recurrence-free survival (RFS). CONCLUSIONS In HCC, intratumoral CXCR2 + cell count is associated with PSMA expression. Intratumoral and benign compartments had different CXCR2 + inflammatory cell makeup. The immune microenvironment of HCC appears to differ depending on underlying risk factors. Further investigations are warranted to elucidate PSMA biology and assess the potential utility of CXCR2 IHC in PSMA-targeted theranostics.
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Affiliation(s)
- Eundong Park
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Nusret Bekir Subasi
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Xin Wang
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Michel Kmeid
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
- Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Anne Chen
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
- Pathology and Immunology, Washington University, St. Louis, MO, USA
| | - Chelsea Tooke-Barry
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Hwajeong Lee
- Pathology and Laboratory Medicine, Albany Medical Center, Mail Code 81, 47 New Scotland Avenue, Albany, NY, 12208, USA.
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Lyu X, Sze KMF, Lee JMF, Husain A, Tian L, Imbeaud S, Zucman-Rossi J, Ng IOL, Ho DWH. Disparity landscapes of viral-induced structural variations in HCC: Mechanistic characterization and functional implications. Hepatology 2025; 81:1805-1821. [PMID: 39270063 PMCID: PMC12077337 DOI: 10.1097/hep.0000000000001087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND AND AIMS HCC is the most common type of primary liver cancer and is a common malignancy worldwide. About half of all new liver cancers worldwide each year occur in China, including Hong Kong, due to a high prevalence of HBV infection. HBV DNA integrates into the human genome, disrupting the endogenous tumor suppressors/regulatory genes or enhancing the activity of proto-oncogenes. It would be useful to examine the different NGS-based databases to provide a more unbiased and comprehensive survey of HBV integration. APPROACH AND RESULTS We aimed to take advantage of publicly available data sets of different regional cohorts to determine the disparity landscapes of integration events among sample cohorts, tissue types, chromosomal positions, individual host, and viral genes, as well as genic locations. By comparing HCC tumors with non tumorous livers, the landscape of HBV integration was delineated in gene-independent and gene-dependent manners. Moreover, we performed mechanistic investigations on how HBV-TERT integration led to TERT activation and derived a score to predict patients' prognostication according to their clonal disparity landscape of HBV integration. CONCLUSIONS Our study uncovered the different levels of clonal enrichment of HBV integration and identified mechanistic insights and prognostic biomarkers. This strengthens our understanding of HBV-associated hepatocarcinogenesis.
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Affiliation(s)
- Xueying Lyu
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Karen Man-Fong Sze
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Joyce Man-Fong Lee
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Abdullah Husain
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Lu Tian
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Sandrine Imbeaud
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- FunGeST lab, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- FunGeST lab, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, Paris, France
| | - Irene Oi-Lin Ng
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Daniel Wai-Hung Ho
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong
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El-Melegy MG, El-Kamel AH, Mehanna RA, Gaballah A, Eltaher HM. Stable self-assembled oral metformin-bridged nanocochleates against hepatocellular carcinoma. Drug Deliv Transl Res 2025; 15:2064-2086. [PMID: 39537911 PMCID: PMC12037436 DOI: 10.1007/s13346-024-01724-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 11/16/2024]
Abstract
Despite its established anti-diabetic activity, Metformin hydrochloride (MET) has been repurposed for the management of hepatocellular carcinoma (HCC). Owing to MET high aqueous solubility and poor oral permeability, a novel nanoplatform is sought to overcome the current challenges of traditional formulations. In this study, we developed MET-bridged nanocochleates (MET-CO) using a direct bridging method followed by optimization and assessment using various in-vitro and in-vivo pharmacokinetic methods. The optimized nanocochleates MET-CODCP 19, containing dicetyl phosphate (DCP), displayed uniform snail-shaped nano-rolls measuring 136.41 ± 2.11 nm with a PDI of 0.241 ± 0.005 and a highly negative ζ-potential of -61.93 ± 2.57 mV. With an impressive MET encochleation efficiency (> 75%), MET-CODCP 19 exhibited a controlled biphasic release profile, with minimal initial burst followed by prolonged release for 24 h. Importantly, they showed significant MET permeation in both in-vitro Caco-2 and ex-vivo intestinal models compared to non-DCP containing formula or MET solution. The in-vivo oral bioavailability study demonstrated pronounced improvements in the pharmacokinetic parameters with a 5.5 relative bioavailability compared to MET solution. Notably, a significant reduction in IC50 values in HepG2 cells after 24 h of treatment was observed. Furthermore, the optimized formulation showed a significant downregulation of anti-apoptotic and cancer stemness genes, with 12- and 2-fold lower expression compared to MET solution. These promising results highlight the efficacy of the novel MET-bridged nanocochleates as a stable nanoplatform for enhancing the oral bioavailability of MET and boosting its anticancer potential against HCC.
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Affiliation(s)
- Mohamed G El-Melegy
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Amal H El-Kamel
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Radwa A Mehanna
- Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Center of Excellence for Research in Regenerative Medicine and Applications CERRMA, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Ahmed Gaballah
- Microbiology Department, Medical Research Institute, Alexandria University, Alexandria, 21561, Egypt
| | - Hoda M Eltaher
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
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Kodali S, Kulik L, D'Allessio A, De Martin E, Hakeem AR, Lewinska M, Lindsey S, Liu K, Maravic Z, Patel MS, Pinato D, Rammohan A, Rich N, Sanduzzi Zamparelli M, Victor DW, Vinaxia C, Brombosz EW, Villanueva A, Meyer T, Selzner N, Ghobrial RM, Rela M, Sapisochin G, and the ILTS ILCA Consensus 2024 Group. The 2024 ILTS-ILCA consensus recommendations for liver transplantation for HCC and intrahepatic cholangiocarcinoma. Liver Transpl 2025; 31:815-831. [PMID: 40014003 DOI: 10.1097/lvt.0000000000000589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Collaborators] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 01/29/2025] [Indexed: 02/28/2025]
Abstract
Liver transplantation (LT) provides the best long-term survival outcomes for patients with liver cancer. As a result, the field of transplant oncology has grown greatly over the past few decades, and many centers have expanded their criteria to allow increased access to LT for liver malignancies. Center-level guidelines and practices in transplant oncology significantly vary across the world, leading to debate regarding the best course of treatment for this patient population. An international consensus conference was convened by the International Liver Transplantation Society and the International Liver Cancer Association on February 1-2, 2024, in Valencia, Spain to establish a more universal consensus regarding LT for oncologic indications. The conference followed the Delphi process, followed by an external expert review. Consensus statements were accepted regarding patient assessment and waitlisting criteria, pretransplant treatment (including immunotherapy) and downstaging, living donor LT, post-LT patient management, and patient- and caregiver-related outcomes. The multidisciplinary participants in the consensus conference provided up-to-date recommendations regarding the selection and management of patients with liver cancer being considered for LT. Although participants deferred to center protocols in many cases, there was great interest in safely expanding access to LT for patients with larger tumor burden and biologically amenable lesions.
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Affiliation(s)
- Sudha Kodali
- JC Walter Transplant Center, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, Texas, USA
- Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Laura Kulik
- Northwestern Medicine, Chicago, Illinois, USA
| | - Antonio D'Allessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Eleonora De Martin
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris-Saclay, Villejuif, France
| | | | - Monica Lewinska
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Gubra, Hørsholm, Denmark
| | | | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
| | | | - Madhukar S Patel
- Department of Surgery, Division of Surgical Transplantation, UT Southwestern Medical Center, Dallas, Texas, USA
| | - David Pinato
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, Tamil Nadu, India
| | - Nicole Rich
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas Texas, USA
| | - Marco Sanduzzi Zamparelli
- BCLC group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Liver Oncology Unit, Liver Unit, Hospital Clínic, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - David W Victor
- JC Walter Transplant Center, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, Texas, USA
- Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Carmen Vinaxia
- Hepatology and Liver Transplantation, Digestive Diseases Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Tim Meyer
- UCL Cancer Institute, University College London, UK
- Royal Free Hospital, London, UK
| | - Nazia Selzner
- Department of Medicine, Division of Gastroenterology, University of Toronto, Toronto, Ontario, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Rafik Mark Ghobrial
- JC Walter Transplant Center, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, Texas, USA
- Department of Surgery, Houston Methodist Hospital, Houston, Texas, USA
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, Tamil Nadu, India
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Surgery, Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
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Collaborators
Maen Abdelrahim, Vatche Agopian, Deniz Balci, Tanios Bekaii-Saab, Marina Berenguer, Prashant Bhangui, Sherrie Bhoori, Jordi Bruix, Albert Chi-Yan Chan, Stephen Chan, Alfred Kow Wei Chieh, François Durand, Bijan Eghtesad, Ahmed Elsabbagh, Karim J Halazun, Taizo Hibi, Milind Javle, Dong Hwan Jung, Korosh Khalili, Jeong Min Lee, Robert J Lewandowski, Pål-Dag Line, Josep M Llovet, Valeria R Mas, Vincenzo Mazzaferro, Neil Mehta, Grainne O'Kane, Valérie Paradis, Neehar Parikh, Anjana Pillai, Wojciech Polak, James Pomposelli, Lorenza Rimassa, Amit Singal, Arvinder Singh Soin, Parissa Tabrizian, Christian Toso, Juan Valle, Eric Vibert, Augusto Villanueva, Arndt Vogel, Kymberly Watt, Andrea Wilson Woods,
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Zhu Y, Liu T, Chen J, Wen L, Zhang J, Zheng D. Prediction of therapeutic response to transarterial chemoembolization plus systemic therapy regimen in hepatocellular carcinoma using pretreatment contrast-enhanced MRI based habitat analysis and Crossformer model. Abdom Radiol (NY) 2025; 50:2464-2475. [PMID: 39586897 DOI: 10.1007/s00261-024-04709-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 11/27/2024]
Abstract
PURPOSE To develop habitat and deep learning (DL) models from multi-phase contrast-enhanced magnetic resonance imaging (CE-MRI) habitat images categorized using the K-means clustering algorithm. Additionally, we aim to assess the predictive value of identified regions for early evaluation of the responsiveness of hepatocellular carcinoma (HCC) patients to treatment with transarterial chemoembolization (TACE) plus molecular targeted therapies (MTT) and anti-PD-(L)1. METHODS A total of 102 patients with HCC from two institutions (A, n = 63 and B, n = 39) who received TACE plus systemic therapy were enrolled from September 2020 to January 2024. Multiple CE-MRI sequences were used to outline 3D volumes of interest (VOI) of the lesion. Subsequently, K-means clustering was applied to categorize intratumoral voxels into three distinct subgroups, based on signal intensity values of images. Using data from institution A, the habitat model was built with the ExtraTrees classifier after extracting radiomics features from intratumoral habitats. Similarly, the Crossformer model and ResNet50 model were trained on multi-channel data in institution A, and a DL model with Transformer-based aggregation was constructed to predict the response. Finally, all models underwent validation at institution B. RESULTS The Crossformer model and the habitat model both showed high area under the receiver operating characteristic curves (AUCs) of 0.869 and 0.877 (training cohort). In validation, AUC was 0.762 for the Crossformer model and 0.721 for the habitat model. CONCLUSION The habitat model and DL model based on CE-MRI possesses the capability to non-invasively predict the efficacy of TACE plus systemic therapy in HCC patients, which is critical for precision treatment and patient outcomes.
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Affiliation(s)
- Yuemin Zhu
- Department of Radiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Tao Liu
- Department of Radiology, Chongqing University Cancer Hospital, Chongqing Cancer Institute, and Chongqing Cancer Hospital, Chongqing, China
| | - Jianwei Chen
- Department of Radiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Liting Wen
- Department of Radiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Jiuquan Zhang
- Department of Radiology, Chongqing University Cancer Hospital, Chongqing Cancer Institute, and Chongqing Cancer Hospital, Chongqing, China.
| | - Dechun Zheng
- Department of Radiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
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Ratiphunpong P, Inmutto N, Angkurawaranon S, Wantanajittikul K, Suwannasak A, Yarach U. A Pilot Study on Deep Learning With Simplified Intravoxel Incoherent Motion Diffusion-Weighted MRI Parameters for Differentiating Hepatocellular Carcinoma From Other Common Liver Masses. Top Magn Reson Imaging 2025; 34:e0316. [PMID: 40249154 DOI: 10.1097/rmr.0000000000000316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/18/2025] [Indexed: 04/19/2025]
Abstract
OBJECTIVES To develop and evaluate a deep learning technique for the differentiation of hepatocellular carcinoma (HCC) using "simplified intravoxel incoherent motion (IVIM) parameters" derived from only 3 b-value images. MATERIALS AND METHODS Ninety-eight retrospective magnetic resonance imaging data were collected (68 men, 30 women; mean age 59 ± 14 years), including T2-weighted imaging with fat suppression, in-phase, out-of-phase, and diffusion-weighted imaging (b = 0, 100, 800 s/mm2). Ninety percent of data were used for stratified 10-fold cross-validation. After data preprocessing, diffusion-weighted imaging images were used to compute simplified IVIM and apparent diffusion coefficient (ADC) maps. A 17-layer 3D convolutional neural network (3D-CNN) was implemented, and the input channels were modified for different strategies of input images. RESULTS The 3D-CNN with IVIM maps (ADC, f, and D*) demonstrated superior performance compared with other strategies, achieving an accuracy of 83.25 ± 6.24% and area under the receiver-operating characteristic curve of 92.70 ± 8.24%, significantly surpassing the baseline of 50% (P < 0.05) and outperforming other strategies in all evaluation metrics. This success underscores the effectiveness of simplified IVIM parameters in combination with a 3D-CNN architecture for enhancing HCC differentiation accuracy. CONCLUSIONS Simplified IVIM parameters derived from 3 b-values, when integrated with a 3D-CNN architecture, offer a robust framework for HCC differentiation.
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Affiliation(s)
- Phimphitcha Ratiphunpong
- Department of Radiologic Technology, Faculty of Associated Medical Science, Chiang Mai University, Chiang Mai, Thailand
- Radiological Technology School, Faculty of Health Science Technology, Chulabhorn Royal Academy, Bangkok, Thailand; and
| | - Nakarin Inmutto
- Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Salita Angkurawaranon
- Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Kittichai Wantanajittikul
- Department of Radiologic Technology, Faculty of Associated Medical Science, Chiang Mai University, Chiang Mai, Thailand
| | - Atita Suwannasak
- Department of Radiologic Technology, Faculty of Associated Medical Science, Chiang Mai University, Chiang Mai, Thailand
| | - Uten Yarach
- Department of Radiologic Technology, Faculty of Associated Medical Science, Chiang Mai University, Chiang Mai, Thailand
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Ge T, Wang Y, Han Y, Bao X, Lu C. Exploring the Updated Roles of Ferroptosis in Liver Diseases: Mechanisms, Regulators, and Therapeutic Implications. Cell Biochem Biophys 2025; 83:1445-1464. [PMID: 39543068 DOI: 10.1007/s12013-024-01611-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2024] [Indexed: 11/17/2024]
Abstract
Ferroptosis, a newly discovered mode of cell death, is a type of iron-dependent regulated cell death characterized by intracellular excessive lipid peroxidation and imbalanced redox. As the liver is susceptible to oxidative damage and the abnormal iron accumulation is a major feature of most liver diseases, studies on ferroptosis in the field of liver diseases are of great interest. Studies show that targeting the key regulators of ferroptosis can effectively alleviate or even reverse the deterioration process of liver diseases. System Xc- and glutathione peroxidase 4 are the main defense regulators of ferroptosis, while acyl-CoA synthetase long chain family member 4 is a key enzyme causing peroxidation in ferroptosis. Generally speaking, ferroptosis should be suppressed in alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver injury, while it should be induced in liver fibrosis and hepatocellular carcinoma. In this review, we summarize the main regulators involved in ferroptosis and then the mechanisms of ferroptosis in different liver diseases. Treatment options of drugs targeting ferroptosis are further concluded. Determining different triggers of ferroptosis can clarify the mechanism of ferroptosis occurs at both physiological and pathological levels.
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Affiliation(s)
- Ting Ge
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yang Wang
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yiwen Han
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
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Wang Y, Wang J, Zhou Z, Gu Y, Zhu X, Yi Z, Cao C, He L, Du Y, Guo H, Tian Y, Fan Z. A read-through circular RNA RCRIN inhibits metabolic dysfunction-associated steatotic liver disease. J Hepatol 2025; 82:1068-1079. [PMID: 39667599 DOI: 10.1016/j.jhep.2024.11.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND & AIMS The molecular mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive and whether non-coding RNAs can serve as biomarkers and therapeutic targets in MASLD has not been determined. METHODS Exon capture RNA-sequencing analysis was used to identify read-through circular RNAs (rt-circRNAs) in livers from three patients with MASLD and three controls without MASLD. Hepatocyte-specific deletion or overexpression of rt-circRNA RCRIN were utilized to study MASLD pathogenesis. RESULTS We identified 1,126 rt-circRNAs in liver tissues from patients with MASLD. RCRIN was highly expressed in normal livers and was downregulated in MASLD livers. Rcrin deletion in hepatocytes caused lipid accumulation and MASLD development, while Rcrin overexpression suppressed MASLD progression. Mechanistically, in normal hepatocytes, highly expressed RCRIN bound to RPL8 protein to recruit RNF2 for its degradation, reducing RPL8-containing ribosome numbers and lipid accumulation. In MASLD livers, low RCRIN expression led to the release of RPL8 protein, increasing RPL8-containing ribosome numbers and lipid synthesis, and leading to greater lipid accumulation and endoplasmic reticulum stress. We synthesized RCRIN and N-acetylgalactosamine (GalNAc)-Rpl8 small-interfering RNAs, which both suppressed the pathogenesis of established MASLD in mice. CONCLUSIONS Our findings reveal an in vivo function of the rt-circRNA RCRIN, show its inhibitory effects in MASLD pathogenesis, and indicate that RCRIN and RPL8 may be therapeutic targets for candidate nucleic acid drugs to treat MASLD. IMPACT AND IMPLICATIONS Our finds reveal a novel mechanism connecting a read-through circular RNA RCRIN, ribosome heterogeneity and metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis. In normal hepatocytes, RCRIN exerts its role by reducing liver lipid accumulation and endoplasmic reticulum stress through promotion of RPL8 degradation. In patients with MASLD, lower RCRIN levels lead to the release of RPL8 to form RPL8-containing ribosomes, promoting lipid accumulation and endoplasmic reticulum stress. RCRIN overexpression and RPL8 depletion dramatically suppress MASLD development and progression. Our findings indicate that RCRIN and RPL8 might be potential therapeutic targets for the treatment of patients with MASLD.
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Affiliation(s)
- Yanying Wang
- Ministry of Education Key Laboratory of Cell Proliferation and Regulation Biology, Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
| | - Jianyi Wang
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Drug Control, Beijing 102206, China
| | - Ziheng Zhou
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yang Gu
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaoxiao Zhu
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhibin Yi
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Changchang Cao
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Lei He
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing 100853, China
| | - Ying Du
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hui Guo
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yong Tian
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Zusen Fan
- Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Finn RS, Gu K, Chen X, Merle P, Lee KH, Bouattour M, Cao P, Wang W, Cheng AL, Zhu L, Lim HY, Kudo M, Pan Y, Chang TT, Edeline J, Li W, Yang P, Li C, Li J, Siegel AB, Qin S. Second-line pembrolizumab for advanced HCC: Meta-analysis of the phase III KEYNOTE-240 and KEYNOTE-394 studies. JHEP Rep 2025; 7:101350. [DOI: 10.1016/j.jhepr.2025.101350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/03/2025] Open
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Song L, Wang Y, Wang C, Yu Z, Wang L, He W, Zhang H, Li X, Zhong S. Integration of Bulk RNA and Single-Cell Analyses Reveal Distinct Expression Patterns of Anoikis-Related Genes and the Immunosuppressive Role of NQO1 + Macrophages in Hepatocellular Carcinoma. FASEB J 2025; 39:e70654. [PMID: 40386974 DOI: 10.1096/fj.202501310r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2025] [Revised: 05/01/2025] [Accepted: 05/09/2025] [Indexed: 05/20/2025]
Abstract
Anoikis resistance plays a crucial role in the proliferation, metastasis, and invasion of hepatocellular carcinoma (HCC). However, the key genes involved remain to be identified. This study aimed to investigate the prognostic value and impact of anoikis-related genes (ARGs) on the immunosuppressive microenvironment in HCC patients through the integration of bulk RNA and single-cell RNA sequencing (scRNA-seq) bioinformatic analysis. An anoikis-related gene risk score model (ARGRS) comprising 11 ARGs was established via machine learning. scRNA-seq was performed to assess the heterogeneity of ARGs in HCC. In vitro experiments were conducted to investigate the effects of NAD(P)H: quinone oxidoreductase 1 (NQO1) on the polarization, phenotype, and function of macrophages. Bioinformatics analysis demonstrated that ARGRS had perfect efficiency in predicting the prognosis of HCC patients and that ARGs potentially play a role in maintaining the invasion and metastasis of malignant cells. Notably, NQO1+ macrophages presented features consistent with alternatively activated macrophages (M2) and displayed a powerful immunosuppressive effect, particularly in close interaction with T cells within the tumor immune microenvironment. Moreover, inhibition of NQO1 expression via dicoumarol resulted in reduced expression of the M2-associated markers CD206 and CD163, as well as the immunosuppressive cytokines IL-10 and TGF-β. Strikingly, this treatment effectively mitigated the immunosuppressive impact of macrophages on T cells. Collectively, ARGs are closely associated with the poor prognosis of HCC patients, and NQO1+ macrophages may have an immunosuppressive effect on HCC, suggesting that intervention in anoikis may represent a potential strategy for HCC treatment.
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Affiliation(s)
- Linnan Song
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Yuhao Wang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Chen Wang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Ziqian Yu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Liping Wang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Weixin He
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Hui Zhang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Xiaoyi Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
| | - Shihong Zhong
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, China
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Xie C, Singal AK. Beyond the Cure: Navigating Hepatocellular Risk and Surveillance after Hepatitis C Eradication in the Direct-acting Antiviral Era. J Clin Transl Hepatol 2025; 13:418-424. [PMID: 40385945 PMCID: PMC12078169 DOI: 10.14218/jcth.2024.00499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 05/20/2025] Open
Abstract
Direct-acting antivirals (DAAs) have dramatically changed the landscape of chronic hepatitis C virus (HCV) treatment and significantly reduced the risk of HCV-related hepatocellular carcinoma (HCC) after achieving sustained virologic response. However, the risk of HCC persists, particularly in patients with pre-treatment cirrhosis or fibrosis stage 3 (F3), even after DAA-induced viral eradication. While professional guidelines agree on the need for surveillance in cirrhotic patients, there is no consensus regarding surveillance for the pre-treatment F3 population following HCV eradication. The risk of HCC in the F3 population falls below the threshold for cost-effective surveillance. However, co-existing risk factors-such as diabetes, hepatic steatosis, alcohol use, advanced age, and elevated alpha-fetoprotein levels-may warrant reconsideration of HCC surveillance in this group. This underscores the need for an individualized, risk-based approach to HCC surveillance. This review provided a simplified algorithm to assist clinicians in managing patients with HCV after DAA-induced sustained virologic response.
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Affiliation(s)
- Chencheng Xie
- Department of Gastroenterology, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
| | - Ashwani K. Singal
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
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Wang C, Shi CH, Bai HY, Lu J, Hu HT, Sun YM, Gao H, An H, Lu JH, Zhao HJ, Zhu ZH. Astragali radix - Curcumae rhizoma herb pair suppresses hepatocellular carcinoma through EGFR/AKT/mTOR pathway and induces lipid peroxidation-related ferroptosis via HIF-1α/HO-1/GPX4 axis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119912. [PMID: 40316156 DOI: 10.1016/j.jep.2025.119912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/25/2025] [Accepted: 04/29/2025] [Indexed: 05/04/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Astragali Radix - Curcumae Rhizoma herb pair (ACHP) originated from the famous traditional Chinese medicine text "YiXueZhongZhongCanXiLu", in which the two herbs were paired to form Chinese herbal compounds commonly used clinically for digestive system tumors, such as hepatocellular carcinoma (HCC). Although ACHP has been inherited for thousands of years in China, its mechanism against HCC remains unclear. AIM OF THE STUDY The study aims to evaluate the effect and explore the mechanism of ACHP against HCC. METHODS The efficacy and safety of ACHP against HCC in vivo were evaluated by tumor volume, organ index, H&E staining, hepatic and renal factors. The serum metabolites of ACHP were identified by UPLC-Q-TOF-MS/MS. The key targets and potential mechanisms of ACHP against HCC were screened by transcriptomics, network pharmacology and molecular docking. The effect and induction of ferroptosis of ACHP-containing serum on HCC in vitro was evaluated by MTT, colony formation assay and specific detection kits. The expression of ferroptosis-related proteins and pathways in vivo was detected by immunohistochemistry. RESULTS ACHP significantly inhibited tumor proliferation compared to the two herbs used separately, and showed a favorable safety profile. A total of 75 serum metabolites were identified in both positive and negative ion modes. Transcriptomics results revealed that ferroptosis played a key role in the anti-HCC process of ACHP. Network pharmacology and molecular docking results suggested that the anti-HCC effect of ACHP may be related to EGFR/AKT/mTOR pathway and HIF-1α/HO-1/GPX4 axis. In vitro and in vivo experiments further demonstrated that ACHP suppressed oncogenic signaling via the EGFR/AKT/mTOR pathway while inducing lipid peroxidation-related ferroptosis through HIF-1α/HO-1/GPX4 axis, thereby inhibiting HepG2 cells proliferation and HCC mice tumor growth. CONCLUSION ACHP exerts its effects by suppressing oncogenic signaling through the EGFR/AKT/mTOR pathway and inducing lipid peroxidation-related ferroptosis in HCC via the HIF-1α/HO-1/GPX4 axis. This systematic investigation establishes a coherent pharmacological chain from compound identification to mechanism verification, highlighting ACHP's therapeutic potential as a ferroptosis inducer targeting oncogenic signaling networks in HCC.
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MESH Headings
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Animals
- Humans
- Proto-Oncogene Proteins c-akt/metabolism
- Ferroptosis/drug effects
- ErbB Receptors/metabolism
- TOR Serine-Threonine Kinases/metabolism
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Mice
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Lipid Peroxidation/drug effects
- Male
- Mice, Inbred BALB C
- Signal Transduction/drug effects
- Mice, Nude
- Antineoplastic Agents, Phytogenic/pharmacology
- Cell Line, Tumor
- Hep G2 Cells
- Rhizome
- Xenograft Model Antitumor Assays
- Astragalus propinquus
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Affiliation(s)
- Chen Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Chen-Hao Shi
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Hao-Yang Bai
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Jun Lu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Hong-Tao Hu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Yu-Mei Sun
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Hang Gao
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Hai An
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Jia-Hui Lu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China
| | - Hua-Jun Zhao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
| | - Zhi-Hui Zhu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
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Ghorbani Vanan A, Nami MT, Ghorbaninezhad F, Eini P, Bagheri K, Mohammadlou M, Mohammadi F, Tahmasebi S, Safarzadeh E. Macrophage polarization in hepatocellular carcinoma: a lncRNA-centric perspective on tumor progression and metastasis. Clin Exp Med 2025; 25:173. [PMID: 40413657 DOI: 10.1007/s10238-025-01711-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Accepted: 05/01/2025] [Indexed: 05/27/2025]
Abstract
Hepatocellular carcinoma (HCC) represents a multifaceted and aggressive cancer frequently associated with chronic inflammation and immune cell activation. The pathogenesis of HCC is influenced by a variety of factors such as long non-coding RNAs (lncRNAs). LncRNAs, a significant class of non-coding RNAs, contribute to the intricate nature of the transcriptome and are extensively distributed across various tissues and cell types in mammals. In HCC, these transcripts are crucial not only for deepening our molecular understanding but also for advancing clinical outcomes, as they serve as both oncogenes and tumor suppressors by dysregulating essential genes and signaling pathways. Additionally, macrophage polarization is crucial in HCC tumor progression. The study explores the role of lncRNAs in hepatocellular carcinoma (HCC) and elucidates the specific molecular mechanisms by which key lncRNAs such as HULC and MALAT1 regulate macrophage polarization in the tumor microenvironment. These lncRNAs modulate cytokine profiles and influence immune regulators including IL-10 and TGF-β, steering macrophages toward an M2-like, pro-tumor phenotype that fosters aggressive tumor characteristics and progression. Mechanistically, these transcripts interact with epigenetic modifiers like EZH2 to alter histone modifications and chromatin accessibility, while also stabilizing mRNAs that encode inflammatory mediators, thereby reinforcing an immunosuppressive response. The clinical implications of these findings are substantial. The detection of such lncRNAs in patient samples offers a minimally invasive diagnostic avenue, while their pivotal role in complex immune cell behavior positions them as promising prognostic biomarkers. Moreover, targeting these lncRNAs may lead to innovative therapeutic strategies aimed at disrupting tumor-supportive inflammatory cascades and restoring an effective antitumor immune response. Understanding the intricate interplay between lncRNA-mediated epigenetic regulation and macrophage polarization not only refines our grasp of HCC progression but also opens new pathways for interventions designed to improve patient outcomes.
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Affiliation(s)
- Ahmad Ghorbani Vanan
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mohammad Taha Nami
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Farid Ghorbaninezhad
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Pooya Eini
- Toxicological Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kamyar Bagheri
- Student Research Committee, Abadan University of Medical Sciences, Abadan, Iran
| | - Maryam Mohammadlou
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Safa Tahmasebi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Elham Safarzadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
- Department of Microbiology, Parasitology, and Immunology, Ardabil University of Medical Sciences, Ardabil, Iran.
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Mo PL, Lin M, Gao BW, Zhang SB, Chen JP. Knowledge structure analysis and network visualization of tumor-associated macrophages in hepatocellular carcinoma research: A bibliometric mapping. World J Clin Oncol 2025; 16:102747. [DOI: 10.5306/wjco.v16.i5.102747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/13/2025] [Accepted: 04/11/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma (HCC). Nevertheless, a comprehensive quantitative analysis of TAMs in HCC remained insufficient. Therefore, the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.
AIM To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.
METHODS The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research. Utilizing the Analysis Platform of Bibliometrics, CiteSpace 6.2.R4, and Vosviewer 1.6.19, the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity, countries of origin, affiliated institutions, publishing journals, contributing authors, co-references, author keywords, and emerging frontiers within this research domain.
RESULTS A thorough examination was undertaken on 818 papers within this particular field, published between January 1, 1985 to September 1, 2023, which has witnessed a substantial surge in scholarly contributions since 2012, with a notable outbreak in 2019. China was serving as the central hub in this field, with Fudan University leading in terms of publications and citations. Chinese scholars have taken the forefront in driving the research expansion within this field. Hepatology emerged as the most influential journal in this field. The study by Qian and Pollard in 2010 received the highest number of co-citations. It was observed that the citation bursts of references coincided with the outbreak of publications. Notably, “tumor microenvironment”, “immunotherapy”, “prognostic”, “inflammation”, and “polarization”, etc. emerged as frequently occurring keywords in this field. Of particular interest, “immune evasion”, “immune infiltration”, and “cancer genome atlas” were identified as emerging frontiers in recent research.
CONCLUSION The field of TAMs in HCC exhibited considerable potential, as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC. The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment, with a focus on how to counter immune evasion and reduce immune infiltration.
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Affiliation(s)
- Ping-Li Mo
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Ming Lin
- Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Bo-Wen Gao
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Shang-Bin Zhang
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Jian-Ping Chen
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
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Oura K, Morishita A, Manabe T, Takuma K, Nakahara M, Tadokoro T, Fujita K, Mimura S, Tani J, Ono M, Sanomura T, Nishiyama Y, Himoto T, Kobara H. Efficacy of olanzapine as an antiemetic drug for transcatheter arterial chemoembolization for hepatocellular carcinoma. Sci Rep 2025; 15:18095. [PMID: 40413249 PMCID: PMC12103546 DOI: 10.1038/s41598-025-01632-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 05/07/2025] [Indexed: 05/27/2025] Open
Abstract
Although the addition of olanzapine to conventional antiemetic therapy has been reported to be useful for systemic chemotherapy with highly emetogenic agents such as cisplatin, no studies have evaluated its efficacy in transcatheter arterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC). We evaluated the antiemetic efficacy of olanzapine in patients with HCC undergoing cisplatin-based TACE. This prospective study included 68 patients with HCC scheduled for cisplatin-based TACE between 2021 and 2022. Patients were divided into two groups: an olanzapine group receiving olanzapine 5 mg plus the conventional triple antiemetic combination and a control group receiving only the conventional triple combination therapy. The incidence of digestive symptoms and adverse events (AEs) in both groups were compared. For TACE-induced nausea and vomiting, the olanzapine group had similar antiemetic complete response (aCR) and complete control (CC) rates at 12 h post-TACE as the control group but significantly higher aCR and CC rates during the delayed-phase after 24 h and better patient satisfaction scores. No significant differences were noted in the occurrence of severe AEs in the two groups. The use of olanzapine, in addition to conventional antiemetics, may be a new standard for patients undergoing cisplatin-based TACE.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan.
| | - Takushi Manabe
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Takayuki Sanomura
- Department of Radiology, Faculty of Medicine, Kagawa University, Kita, Kagawa, Japan
| | - Yoshihiro Nishiyama
- Department of Radiology, Faculty of Medicine, Kagawa University, Kita, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
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Hamdy NM, Sallam AAM, Elazazy O, Kabel AM, Salama RM, Gouhar SA, El-Daly SM, Darwish SF. LincRNA-miR interactions in hepatocellular carcinoma: comprehensive review and in silico analysis: a step toward ncRNA precision. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04285-7. [PMID: 40410550 DOI: 10.1007/s00210-025-04285-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 05/09/2025] [Indexed: 05/25/2025]
Abstract
The most prevalent form of primary liver cancer and one of the chief drivers of cancer-related mortality globally is hepatocellular carcinoma (HCC). Imminent evidence has indicated that non-coding RNAs (ncRNAs) play an integral part in the development and propagation of HCC. RNA stabilization, transcription regulation, chromatin and genomic architecture remodeling, enhancer-associated activity, and other varied properties set long intergenic ncRNA (lincRNA) genes apart from messenger RNA (mRNA)-encoding genes. Through a variety of processes, lincRNAs may generally be used to fine-tune the transcription of nearby genes with exceptional tissue specificity, underscoring our quickly developing knowledge of the non-coding genome. Through their binding with divergent cell targets, some HCC-related ncRNAs have been demonstrated to exhibit abnormal expression, contribute to malignant growth, evade apoptosis, and have invasive potential. Therefore, a better comprehension of lincRNA dysregulation might offer novel perspectives on the pathophysiology of HCC as well as innovative instruments for the early detection and management of HCC. In the present review, we provide an overview of the increasing relevance of lincRNAs as a major contributor to the pathophysiology of HCC, emphasizing their influence on signaling pathways implicated in the development, progression, and response to treatment of tumors. In addition, we go over the new approaches that target lincRNAs for HCC treatment as well as the possible therapeutic uses of lincRNAs as prognostic and diagnostic biomarkers for HCC.
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Affiliation(s)
- Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo, 11566, Egypt.
| | - Al-Aliaa M Sallam
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo, 11566, Egypt
- Biochemistry Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ola Elazazy
- Biochemistry Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed M Kabel
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rania M Salama
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt
| | - Shaimaa A Gouhar
- Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, 12622, Egypt
| | - Sherien M El-Daly
- Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, 12622, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Giza, 12622, Egypt
| | - Samar F Darwish
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
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Xu Y, Lan F, Bi Q, Li X, Wang Z, Li Y, Li P, Long H, Du L. Comprehensive analysis of the prognosis and tumor immune microenvironment of ubiquitin-conjugating enzyme transport-related gene UBE2C in hepatocellular carcinoma. Discov Oncol 2025; 16:884. [PMID: 40410642 PMCID: PMC12102447 DOI: 10.1007/s12672-025-02675-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 05/12/2025] [Indexed: 05/25/2025] Open
Abstract
Ubiquitin-conjugating enzyme E2 C (UBE2C) is involved in tumor progression and cellular processes in many cancers and is implicated in cell cycle regulation. However, its prognostic significance in Hepatocellular carcinoma (HCC) and the mechanism of tumor immune response are unknown. The expression of UBE2C genes in HCC and normal tissue samples was investigated based on The Cancer Genome Atlas (TCGA) LIHC dataset and validated by Gene Expression Omnibus and Human Protein Atlas. Subsequently, the relationship between UBE2C gene expression, clinicopathologic parameters, and each survival period was investigated by regression analysis and Kaplan-Meier survival curves. The set of genes co-expressed with UBE2C was constructed and subjected to genomic enrichment analysis, GO and KEGG pathway enrichment analysis. Finally, the relationship between UBE2C gene expression and immune cell infiltration, immunosuppressive molecules in tumor samples from the TCGA-LIHC dataset was investigated. UBE2C gene expression levels were significantly higher in HCC samples compared to normal samples (p < 0.05). Higher UBE2C gene expression was closely associated with higher tumor grade and later tumor stage. The results of Kaplan-Meier survival curves showed that the survival of HCC patients with high UBE2C expression was shorter than that of patients with low UBE2C expression (p < 0.05, HR(CI) = 1.870[1.276, 2.741]). The results of PPI showed a high correlation between cell cycle-related proteins and UBE2C gene expression. Additionally, the highly expressed UBE2C gene was associated with an increased number of immunosuppressive molecules. UBE2C is an independent predictive marker for HCC patients, and the prognostic value of survival is improved when combined with clinical stage information. This study reveals its potential as a prognostic biomarker and as a new target for HCC intervention.
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Affiliation(s)
- Yang Xu
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China
| | - Fei Lan
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China
| | - Qiang Bi
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China
| | - Xinyi Li
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China
| | - Zhiyu Wang
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China
| | - Ying Li
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China
| | - Pengfei Li
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China.
| | - Haichen Long
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China.
| | - Li Du
- College of Medicine, Tarim University, Alar, 843300, Xinjiang, China.
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Annadurai P, Isaac AE. Unveiling the role of IL7R in metabolism-associated fatty liver disease leading to hepatocellular carcinoma through transcriptomic and machine learning approaches. Discov Oncol 2025; 16:873. [PMID: 40408005 PMCID: PMC12102058 DOI: 10.1007/s12672-025-02638-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 05/09/2025] [Indexed: 05/26/2025] Open
Abstract
Dysregulation of hepatic metabolism is a crucial factor in the development of fatty liver disease and significantly increases the risk of hepatocellular carcinoma (HCC). This study aims to identify the genes implicated in the prognosis of HCC among individuals suffering from metabolic fatty liver disease. We analysed protein-protein interaction (PPI) networks and constructed a weighted gene co-expression network analysis (WGCNA) using high-throughput gene expression profiling datasets. Our meta-analysis uncovered 442 differentially expressed genes (DEGs), comprising 30 upregulated and 412 downregulated genes. We constructed a PPI network from the DEGs and identified significant hub genes based on their degree centrality scores. Additionally, WGCNA highlighted impactful genes and tightly correlated modules, leading to the creation of a gene interaction network specific to metabolism-associated fatty liver disease (MAFLD). Pathway analysis revealed the candidate regulatory gene interleukin-7 receptor (IL7R), which is involved in cytokine-mediated signalling across both interaction networks. Pro-inflammatory cytokines interact with IL7R, activating the JAK/STAT pathway that influences gene expression throughout progression to HCC. IL7R activates STAT3, affecting the behaviour of activated hepatic stellate cells following initial liver damage. Furthermore, the expression of the IL7R gene was validated as a predictor of HCC malignancy through a logistic regression model, resulting in an accuracy of 92%. Findings suggest that IL7R could be the target gene associated with metabolism-linked HCC. It could significantly impact the management of metabolic-associated fatty liver disease (MAFLD) and may help enhance HCC diagnostics to improve patient outcomes.
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Affiliation(s)
- Priyadharshini Annadurai
- Bioinformatics Programming Laboratory, Department of Bioscience, School of Bio Science and Technology, Vellore Institute of Technology, Katpadi, Vellore - 632014, Tamil Nadu, India
| | - Arnold Emerson Isaac
- Bioinformatics Programming Laboratory, Department of Bioscience, School of Bio Science and Technology, Vellore Institute of Technology, Katpadi, Vellore - 632014, Tamil Nadu, India.
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Huang M, Li D, Xia Z, Liao S, Si W, Yuan C, Liao Y, Wu W, Jiang M, Yu X, Quan Y. Silencing NRF2 enhances arsenic trioxide-induced ferroptosis in hepatocellular carcinoma cells. PLoS One 2025; 20:e0322746. [PMID: 40402956 PMCID: PMC12097587 DOI: 10.1371/journal.pone.0322746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 03/26/2025] [Indexed: 05/24/2025] Open
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with high mortality rates partially due to limited therapeutic options and drug resistance. Arsenic trioxide (ATO), a compound clinically proven for acute promyelocytic leukemia (APL), has garnered attention for its emerging efficacy in solid tumors, including HCC. However, the molecular mechanisms driving ATO's antitumor activity in HCC remain incompletely understood. In this study, we aimed to elucidate the ferroptosis-dependent effects of ATO on HCC and and propose a potential therapeutic strategy. METHODS The response of HCC cells to ATO was evaluated using cell viability, wound healing, colony formation, Transwell migration assays, and cell cycle analysis. ATO-induced ferroptosis was assessed by measuring lipid peroxidation (via C11-BODIPY staining), intracellular iron levels, and malondialdehyde (MDA) production. Western blotting was performed to quantify protein levels of NRF2, HO-1, SLC7A11, and GPX4; immunofluorescence staining was employed to determine NRF2 subcellular localization. RESULTS ATO exhibited significant cytotoxicity and inhibited the progression of HCC cells. Treatment with ATO resulted in a notable increase in lipid ROS and MDA levels, which were subsequently reversed by the ferroptosis inhibitors Fer-1 and DFO. Mechanistically, ATO induced ferroptosis by inhibiting GPX4. Furthermore, NRF2 and its downstream targets, HO-1 and SLC7A11, were upregulated during ferroptosis. NRF2 knockdown enhanced lipid peroxidation and ATO-induced cell death. CONCLUSIONS ATO significantly promoted ferroptosis in HCC cells, and NRF2 knockdown enhanced the cytotoxic effects of ATO.
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Affiliation(s)
- Mi Huang
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
- Department of Oncology, The First People’s Hospital of Zhaoqing Affiliated to Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Duanzhuo Li
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
- Department of Oncology, The First People’s Hospital of Zhaoqing Affiliated to Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Zhengzhen Xia
- Department of Oncology, The First People’s Hospital of Zhaoqing Affiliated to Zhaoqing Medical College, Guangdong, People’s Republic of China
- The First Clinical Medical School, Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China
| | - Shengjie Liao
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Wenxia Si
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Chao Yuan
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Yanli Liao
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Weibin Wu
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Minshu Jiang
- The First Clinical Medical School, Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China
| | - Xin Yu
- Department of Scientific Research and Experiment Center, Zhaoqing Medical College, Guangdong, People’s Republic of China
| | - Yi Quan
- Department of Oncology, The First People’s Hospital of Zhaoqing Affiliated to Zhaoqing Medical College, Guangdong, People’s Republic of China
- The First Clinical Medical School, Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China
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Chen L, Li W, Zai W, Zheng X, Meng X, Yao Q, Li W, Liang Y, Ye M, Zhou K, Liu M, Yang Z, Mao Z, Wei H, Yang S, Shi G, Yuan Z, Yu W. HBV sequence integrated to enhancer acting as oncogenic driver epigenetically promotes hepatocellular carcinoma development. J Exp Clin Cancer Res 2025; 44:155. [PMID: 40405227 PMCID: PMC12096768 DOI: 10.1186/s13046-025-03413-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Accepted: 05/09/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND HBV integration is considered as the main contributor to hepatocellular carcinoma (HCC). However, whether HBV integrated sequences determine genotype pathogenicity and how to block their function during HCC progression remains unclear. METHODS An in vitro HBV-infected PHH model and liver cancer cell lines were established to confirm the pathogenic potential of HBV-SITEs. The roles of HBV-SITE-1 in HCC development were analyzed using cellular phenotypic assays and molecular biology techniques, including the combined analysis of RNA-seq and ChIP-seq. Animal models were also used to evaluate the therapeutic effect of HBV-miR-2 inhibitors. RESULTS We identified nine fragments of HBV Sequences Integrated To Enhancer, termed as "HBV-SITEs". Particularly, a single nucleotide variation (T > G) was embedded at seed sequence of HBV-miR-2 in the highest integrated HBV-SITE-1 between genotypes B and H. Unexpectedly, B-HBV-SITE-1, not H-HBV-SITE-1, could abnormally activate oncogenic genes including TERT and accelerate HCC cell proliferation and migration. Meanwhile, HBV-miR-2 was gradually increased in HBV-infected cells and patient plasma with different HCC stages. Importantly, 227 genes upregulated by HBV, were also activated by HBV-miR-2 through triggering HBV-SITE-1 enhancer. Conversely, enhancer activities were particularly decreased by HBV-miR-2 inhibitors, and further downregulated activated oncogenic genes. Finally, HCC growth was dramatically restrained and HBV-induced transcripts were systematically reduced via injection of HBV-miR-2 inhibitors in animal models. CONCLUSION HBV-SITEs were identified as novel oncogenic elements for HCC, which provides an insightful perspective for the other cancers caused by oncogenic DNA viruses. We demonstrated that the integrated HBV sequence itself acted as oncogenic enhancers and nucleotide variations of HBV genotypes account for particular pathogenic progression, supporting that the viral nucleotide sequences are vital pathogenic substances beyond viral proteins. And modulation of their enhancer activities could be clinically achievable strategy for blocking DNA viruses-related cancer progression in the future.
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Affiliation(s)
- Lu Chen
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenxuan Li
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenjing Zai
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiangyi Zheng
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xianlong Meng
- Department of Liver Surgery and Transplantation, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qunyan Yao
- Department of Liver Surgery and Transplantation, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Li
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ying Liang
- Precision Pharmacy and Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Mu Ye
- Department of Liver Surgery and Transplantation, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kaicheng Zhou
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Mengxing Liu
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhicong Yang
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhanrui Mao
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongyan Wei
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuai Yang
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China.
- Research and Development Department, Shanghai Epicurer Biotechnology Co., Ltd., Shanghai, China.
| | - Guoming Shi
- Department of Liver Surgery and Transplantation, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Wenqiang Yu
- Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China.
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