Pien Tze Huang (PTH), a well-established traditional Chinese medicine compound, has exhibited anti-hepatic fibrosis properties both in vitro and in vivo animal models, but the randomized clinical trials to evaluate anti-hepatic fibrosis efficacy of PTH are deficient. Chronic hepatitis B (CHB) is a leading cause of hepatic fibrosis in China. Although antiviral therapies have demonstrated significant effectiveness in arresting the progression of fibrotic disease, complete regression of established fibrosis is limited to only a subset of treated patients.

To assess the efficacy of PTH in improving hepatic fibrosis in CHB patients.

We conducted a randomized, double-blind, placebo-controlled clinical trial involving 144 CHB patients with hepatic fibrosis. This study was carried out from September 2020 to April 2023. (Clinical Trials Registration: ChiCTR2000035128) METHODS: CHB patients with an Ishak score of 2-5 points were recruited from ten hospitals across China. Participants were randomized in 1:1 ratio to receive either oral PTH (0.6 g per dose, three times/day) or placebo for 48 weeks, in addition to the standard treatment of entecavir (0.5 mg/day). The primary endpoint was the change in Ishak score. Secondary outcomes included changes in Knodell HAI score, liver stiffness measurement, AST- to -platelet ratio index, Fibrosis-4 index and hepatic function indices.

Of the 144 randomized patients, 142 patients (71 in the PTH group and 71 in the placebo group) were included in the primary analysis. The PTH group exhibited lower Ishak score compared to the control group (2.37 ± 0.94 vs. 2.87 ± 1.04, F = 6.072, p = 0.015). Notably, in treatment-naive patients, the PTH group showed significant improvement in Ishak score post-treatment compared with the control group (2.13 ± 0.72 vs. 2.74 ± 1.07, F = 6.336, p = 0.014). However, no significant changes were observed in these parameters among patients already receiving antiviral therapy.

The combination of PTH and entecavir demonstrates significant improvement in hepatic fibrosis among CHB patients, especially those who are treatment-naive patients.

Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.

Liver fibrosis is a chronic fibrosing hepatic disorder following recurrent injury, characterized by the excessive accumulation of extracellular matrix. Early detection has a great clinical impact because 80-90% of hepatocellular carcinomas are known to develop in fibrotic or cirrhotic (end-stage fibrotic) livers. PET imaging with FAP ligands exhibited highly promising results in recent years to visualize fibrosis in various organs due to the crucial role of activated fibroblasts in fibrosing processes. However, still little is known about the efficacy of FAP imaging in liver fibrosis. Thus, we sought to investigate the potential of FAPI-PET in a cohort of oncological and non-oncological patients.

199 patients who underwent FAPI-PET/CT at the University Hospital of Heidelberg between July 2017 and July 2020 were retrospectively analyzed. The tracer uptake of the liver was analyzed and correlated with radiological and clinical parameters.

We observed a weak but significant negative correlation between the hepatic FAPI uptake and CT density (r = - 0.273, P < 0.001***). A positive correlation was observed between hepatic FAPI uptake and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) (r = 0.183, P = 0.009**), an established surrogate for liver fibrosis. The liver SUV (standardized uptake value) mean and SUVmax of FAPI showed significant differences between groups of patients with low (< 0.5), middle (0.5-1.0) and higher (> 1.0) levels of APRI (both P < 0.001***).

These preliminary observational results suggest that FAPI-PET may be a viable non-invasive method to asses liver fibrosis.

Cancers represent a significant global health concern, being among the most prevalent malignancies and contributing substantially to morbidity and mortality rates. Notably, colorectal, gastric, pancreatic, and liver cancers are the most frequently diagnosed among these malignancies. The pathogenesis of gastrointestinal (GI) cancers is multifactorial, encompassing a complex interplay of genetic predispositions, environmental exposures, and lifestyle choices. Despite advances in diagnostic approaches and therapeutic strategies, existing treatment modalities, particularly in the advanced stages of these cancers, remain ineffective. Recent research efforts have increasingly focused on the identification and characterization of novel biomarkers that could enhance both the detection and treatment of gastrointestinal cancers. One particularly promising area of investigation involves neuropilins (NRPs). NRPs are involved in essential biological processes such as angiogenesis, cellular migration, and tumor cell-microenvironment interactions, all of which promote tumor progression and contribute to the development of treatment resistance. Overexpression of neuropilins has been linked to poor prognosis in patients, implying that they could be useful in diagnosis and serve as targets for molecular treatment. Recent research also suggests that inhibiting neuropilin activity may slow tumor growth and inhibit angiogenic processes, opening up new possibilities for targeted therapeutic techniques in the treatment of gastrointestinal malignancies.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors of the digestive system, and its prevalence is currently increasing. The current study aims to elucidate the mechanism by which membrane-associated RING-CH8 (MARCH8) impedes the progression of HCC. MARCH8 was identified as a distinct prognostic marker for recurrence-free survival (RFS) and overall survival (OS) in patients with HCC. This study shows that MARCH8 hinders lipid deposition by suppressing the expression of key enzymes for the de novo synthesis of fatty acids (FAs) via RNA sequencing, untargeted metabolomics, and a series of in vivo and in vitro experiments. Further experimental validation demonstrated that MARCH8 was a novel E3 ligase of sterol regulatory element binding protein 1 (SREBP1). And, it primarily promoted the degradation of SREBP1, thereby suppressing the expression of key enzymes involved in the de novo synthesis of FAs. In conclusion, this study has identified MARCH8 as a key "switch" that can be targeted to prevent de novo FA synthesis in HCC cells. This finding may have substantial implications for discovering innovative therapeutic strategies for HCC.

The effectiveness of immunotherapy in hepatocellular carcinoma (HCC) is limited, however, the molecular mechanism remains unclear. In this study, we identified baculoviral IAP repeat-containing protein 2 (BIRC2) as a key regulator involved in immune evasion of HCC.

Genome-wide CRISPR/Cas9 screening was conducted to identify tumor-intrinsic genes pivotal for immune escape. In vitro and in vivo models demonstrated the role of BIRC2 in protecting HCC cells from immune killing. Then the function and relevant signaling pathways of BIRC2 were explored. The therapeutic efficacy of BIRC2 inhibitor was examined in different in situ and xenograft HCC models.

Elevated expression of BIRC2 correlated with adverse prognosis and resistance to immunotherapy in HCC patients. Mechanistically, BIRC2 interacted with and promoted the ubiquitination-dependent degradation of NFκB-inducing kinase (NIK), leading to the inactivation of the non-canonical NFκB signaling pathway. This resulted in the decrease of major histocompatibility complex class I (MHC-I) expression, thereby protecting HCC cells from T cell-mediated cytotoxicity. Silencing BIRC2 using shRNA or inhibiting it with small molecules increased the sensitivity of HCC cells to immune killing. Meanwhile, BIRC2 blockade improved the function of T cells both in vitro and in vivo. Targeting BIRC2 significantly inhibited tumor growth, and enhanced the efficacy of anti-programmed death protein 1 (PD-1) therapy.

Our findings suggested that BIRC2 blockade facilitated immunotherapy of HCC by simultaneously sensitizing tumor cells to immune attack and boosting the anti-tumor immune response of T cells.

Nanotechnology has great potential and advantages in the treatment of hepatocellular carcinoma (HCC), but the research trends and future directions are not yet clear.

Analyze the development trajectory, research hotspots, and future trends of nanotechnology and HCC research globally in the past 20 years, providing a more comprehensive and intuitive reference for researchers in this field.

Retrieve relevant literature on nanotechnology and HCC research in the Web of Science (WOS) Core Collection database, and conduct bibliometric analysis using software such as CiteSpace, VOSviewer, and SCImago Graphica.

A total of 852 English publications meeting the criteria were retrieved from the WOS database, with an overall increasing trend in the number of publications and citation frequency over the years. China leads in the number of publications and international collaborations, followed by the USA and India. The most influential research institution is the Chinese Academy of Sciences, the most influential scholar/team is the Rahman, Mahfoozur team, and the journal with the most publications is the International Journal of Nanomedicine. A comprehensive analysis reveals that the current main research directions include new types of nanoparticles, targeted drug delivery systems, photothermal/photodynamic therapy, gene delivery systems, diagnostics, and imaging. It is anticipated that further collaboration among scholars, institutions, and countries will accelerate the development of nanotechnology in the field of HCC research.

This study provides an in-depth analysis of the research status and development trends of nanotechnology in treating HCC from a bibliometric perspective, offering possible guidance for researchers to explore hot topics and frontiers, select suitable journals, and partners in this field.

The risk of HCC is twice as high in diabetic patients compared to non-diabetic ones, suggesting that diabetes advances carcinogenesis in the liver through a variety of mechanisms. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve liver outcomes, emerging as promising agents to treat hepatocellular carcinoma (HCC) in patients with type 2 diabetes mellitus (T2DM).

We searched PubMed and Scopus databases for articles presenting an association between SGLT2is and HCC to explore the putative mechanisms of action underlying the anti-proliferative activity of SGLT2is.

A total of 24 articles were selected for inclusion, of which 14 were preclinical and 10 were clinical. Preclinical studies were mainly focused on canagliflozin, used alone or in combination with other drugs.

Overall, canagliflozin had a negative effect on HCC cell proliferation by interfering with glucose-dependent and independent metabolic pathways, negatively impacting angiogenesis, and inducing apoptosis in in-vitro cell models. In-vivo, a protective effect on hepatic steatosis and fibrosis and HCC development has been reported. Human studies showed a lower risk of developing HCC in patients on SGLT2is. However, this is supported by retrospective cohort studies. Clinical trials are needed to confirm the causal relationship between SGLT2i administration and HCC development.

Proteins play a central role in regulating biological functions, and various pathways regulate their synthesis and secretion. Endoplasmic reticulum-associated protein degradation (ERAD) is crucial for monitoring protein synthesis and processing unfolded or misfolded proteins in actively growing tumor cells. However, the role of the multiple ERAD complexes in liver cancer remains unclear.

To elucidate the effects of SEL1L-mediated ERAD on Huh7 and explore the underlying mechanisms in vivo and in vitro.

Huh7 cells were treated with ERAD inhibitor to identify ERAD's role. Cell counting kit-8, 5-ethynyl-2'-deoxyuridine and colony formation experiments were performed. Apoptosis level and migration ability were assessed using fluorescence activated cell sorting and Transwell assay, respectively. Huh7 SEL1L knockout cell line was established via clustered regularly interspaced short palindromic repeats, proliferation, apoptosis, and migration were assessed through previous experiments. The role of SEL1L in vivo and the downstream target of SEL1L were identified using Xenograft and mass spectrometry, respectively.

The ERAD inhibitor suppressed cell proliferation and migration and promoted apoptosis. SEL1L-HRD1 significantly influenced Huh7 cell growth. SEL1L knockout suppressed tumor cell proliferation and migration and enhanced apoptosis. Mass spectrometry revealed EXT2 is a primary substrate of ERAD. SEL1L knockout significantly increased the protein expression of EXT2. Furthermore, EXT2 knockdown partially restored the effect of SEL1L knockout.

ERAD inhibition suppressed the proliferation and migration of Huh7 and promoted its apoptosis. EXT2 plays an important role and ERAD might be a potential treatment for Huh7 hepatocellular carcinoma.

Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.

Metabolic dysfunction-associated steatotic liver diseases (MASLD), also known as non-alcoholic fatty liver diseases (NAFLD), have become a leading risk factor for hepatocellular carcinoma (HCC) in Western countries. NAFLD progresses from simple steatosis to HCC, with advanced liver fibrosis (ALF) and metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) representing the two preceding high-risk stages.

We analysed changes in the DNA methylation landscape from simple steatosis to ALF or NASH and determined their relevance in gene regulation and HCC survival. Methylomic datasets generated from applying the Illumina 450K BeadChip on human MASLD/NAFLD liver samples were analysed using integrative data analyses to identify differentially methylated regions (DMRs) associated with ALF (F3/4 vs. F0/1) or non-fibrotic NASH (NASH-F0/1 vs. NAFLD-F0/1).

Gene Set Enrichment Analysis (GSEA) of genes associated with fibrosis-DMRs showed enrichment in xenobiotic metabolism, UV response and hypoxia pathways. Expression of 25 DMR-associated genes showed significant associations with HCC survival outcomes, including 16 genes with fibrosis-DMRs and 2 with NASH-DMRs mapped to their promoter regions. Binding motifs of seven transcription factors (TFs) were enriched in fibrosis-DMRs. Four DMR-associated genes (ESR1, TYW3, CLGN and TUBB) displayed an inverse relationship between promoter methylation and gene expression during human MASLD progression, which was further validated in a mouse MASLD model.

We propose a model in which changes in promoter DNA methylation during NAFLD progression regulate gene expression, impacting HCC survival outcomes.

Hepatic arterial infusion chemotherapy (HAIC) is an advanced targeted therapeutic approach for hepatocellular carcinoma (HCC), the most common type of primary liver cancer. HAIC has demonstrated significant potential in managing advanced HCC, particularly in regions with high prevalence rates. Despite its promise, several challenges and areas for future research remain. Clinical studies have substantiated the efficacy of HAIC in enhancing survival outcomes for patients with advanced hepatic carcinoma. Notably, combination therapies involving immune checkpoint inhibitors, such as lenvatinib and programmed death-1 inhibitors, have shown substantial improvements in median overall survival and progression-free survival compared to systemic chemotherapy. These combination therapies have also exhibited superior response rates and disease control, with manageable and often less severe adverse events relative to systemic treatments. This article is based on the review by Zhou et al and aims to discuss the current status and future directions in the treatment of HCC, emphasizing the role of HAIC and its integration with novel therapeutic agents.

Aging is a natural process that affects the majority of organs within the organism. The liver, however, plays a pivotal role in maintaining the organism's homeostasis due to its robust regenerative and metabolic capabilities. Nevertheless, the liver also undergoes the effects of aging, which can result in a range of metabolic disorders. The function of extracellular vesicles and the signals they convey represent a significant area of interest within the field of ageing research. However, research on liver ageing from the perspective of EVs remains relatively limited.

In the present study, we extracted liver tissue small extracellular vesicles (sEVs) of mice at different ages and performed transcriptome and proteome analyses to investigate the senescence-associated secretory phenotype (SASP) and mechanisms. sEVs in the older group were rich in miR-23b-3p, which was abundant in the sEVs of induced aging cells and promoted cell senescence by targeting TNF alpha induced protein 3 (Tnfaip3). After injecting adeno-associated virus (AAV) expressing miR-23b-3p into mice, the liver of mice in the experimental group displayed a more evident inflammatory response than that in the control group. Additionally, we found elevated miR-23b-3p in blood-derived-sEVs from patients with familial hypercholesterolemia.

Our findings suggest that miR-23b-3p plays a pivotal role in liver aging and is associated with abnormal lipid metabolism. The upregulation of miR-23b-3p in liver EVs may serve as a potential biomarker for aging and metabolic disorders. Targeting miR-23b-3p could provide new therapeutic strategies for ameliorating age-related liver dysfunction and associated metabolic abnormalities.

Embolic and ablative locoregional therapies (LRTs) for hepatocellular carcinoma are widely used to cure, bridge, or downstage patients for more definitive therapies. Common ablative therapies include microwave ablation and radiofrequency ablation, while embolic options include transarterial chemoembolization and 90Y transarterial radioembolization. While these therapies can be highly effective for the appropriate stage of disease, LRTs can suffer from a high rate of posttreatment recurrences. Considerations for administration of specific therapies include disease burden and underlying liver function. Recent data on concomitant or adjuvant systemic therapy, with LRT, have the potential to improve disease control and improve outcomes in this high-risk patient population.

Personalized neoantigen cancer mRNA vaccines are promising candidates for precision medicine. However, the difficulty of identifying neoantigens heavily hinders their broad applicability. This study developed a universal strategy of anti-tumor mRNA vaccine by harnessing "off-the-shelf" immunity to known antigens. First, the model antigen ovalbumin (OVA) is used for mRNA vaccine design. In vitro test indicated that this mRNA vaccine reprogrammed tumor cells that can be recognized and killed by OVA-specific cytotoxic T lymphocytes (CTLs). In situ mRNA vaccine notably inhibited tumor growth across three subcutaneous solid tumor models in mice. Further single-cell sequencing analyses revealed that mRNA vaccination act to reshape the immunosuppressive tumor microenvironment (TME) toward more proinflammatory characteristics. Strikingly, this framework of mRNA-based strategy can be applied to two clinical pathogen antigens, hepatitis B surface antigen (HBsAg), and SARS-CoV-2 spike receptor-binding domain (SRBD). Interestingly, the mRNA-based strategy largely recapitulated the scenario of spontaneous cancer regression following pathogen infection or vaccination. Collectively, this study provides not only proof of concept for universal anti-tumor mRNA therapy, but also mechanistic insights in echoing the long-standing puzzle of spontaneous cancer regression.

Viral infections are established contributors to oncogenesis, leading to significant public health challenges. This systematic review aims to synthesize current knowledge on the mechanisms of viral cellular transformation and their association with various cancers.

Studies reveal key mechanisms of oncogenesis, including direct viral integration into the host genome, expression of viral oncogenes, and indirect pathways such as chronic inflammation and immune evasion. Notably, Human Papillomavirus (HPV) was linked predominantly to cervical and oropharyngeal cancers, while Epstein-Barr Virus (EBV) was associated with lymphomas. Hepatitis B and C viruses were linked to liver cancer, highlighting the diverse impacts of viral infections on oncogenic processes.

This review underscores the complexity of viral interactions with host cells and their implications for cancer development. Findings suggest that targeted interventions, such as vaccination and antiviral therapies, may play a crucial role in reducing the incidence of virus-related cancers. Further research is needed to explore novel therapeutic strategies and the role of co-factors in viral oncogenesis.

Liver cancer is one of the most challenging malignancies, often associated with poor prognosis and limited treatment options. Recent advancements in nanotechnology and artificial intelligence (AI) have opened new frontiers in the fight against this disease. Nanotechnology enables precise, targeted drug delivery, enhancing the efficacy of therapeutics while minimizing off-target effects. Simultaneously, AI contributes to improved diagnostic accuracy, predictive modeling, and the development of personalized treatment strategies. This review explores the convergence of nanotechnology and AI in liver cancer treatment, evaluating current progress, identifying existing research gaps, and discussing future directions. We highlight how AI-powered algorithms can optimize nanocarrier design, facilitate real-time monitoring of treatment efficacy, and enhance clinical decision-making. By integrating AI with nanotechnology, clinicians can achieve more accurate patient stratification and treatment personalization, ultimately improving patient outcomes. This convergence holds significant promise for transforming liver cancer therapy into a more precise, individualized, and efficient process. However, data privacy, regulatory hurdles, and the need for large-scale clinical validation remain. Addressing these issues will be essential to fully realizing the potential of these technologies in oncology.

Food insecurity (FI) is associated with several known hepatocellular carcinoma (HCC) risk factors, but few studies have directly examined FI in association with HCC risk. We aimed to investigate whether county-level FI is associated with HCC risk. We used data from 21 registries in the Surveillance Epidemiology and End Results database to obtain county-level counts of HCC cases from 2018 to 2021. We obtained the county-level FI rates for 2018-2021 from Feeding America's Map the Meal Gap. We used multi-level Poisson regression models with robust standard errors to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Overall, a one-standard-deviation (SD) increase in county-level FI was associated with an 8% increase in HCC risk in the fully adjusted model (IRR = 1.08, 95% CI = 1.06, 1.10). When stratified by age at diagnosis, a one-SD increase in county-level FI was associated with a 2% higher risk of HCC in the ≥65 age group (IRR = 1.02, 95% CI = 1.00, 1.05) and a 15% higher risk in the <65 age group (IRR = 1.15, 95% CI = 1.11, 1.19; interaction p-value < 0.001). If confirmed in other studies, these findings support the need for interventions and policies addressing FI in populations at increased risk for HCC.

Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target.

Hepatocellular carcinoma (HCC), theseventh most common cancer worldwide, is characterized by a high mortality rate, advanced diagnosis, and susceptibility to extrahepatic metastasis. Numerous studies have shown that DNA methylation is a crucial factor in epigenetic modifications and regulation of carcinogenesis.

HCC patient data were sourced from the TCGA dataset as a training set, while GSE116174 was used as an external validation set for verification. Differential methylation and expression analyses were performed on HCC samples with and without extrahepatic metastasis. In the intersecting genes, the relationship between methylation and expression levels of the intersecting genes was analyzed. Genes with a correlation coefficient≥|0.30| and P<0.05 were identified as methylation driver genes. Cox regression analysis was conducted to identify genes associated with HCC prognosis and establish a risk score. Subsequently, a prognostic model was established and validated using Cox regression analysis incorporating the risk score and other clinical factors. Using immunohistochemistry to evaluate the expression of DHX58 and EIF5A2 in HCC tissues with and without extrahepatic metastasis. Immunoinfiltration analysis was performed on the HCC samples using CIBERSORT.

Our research identified eight methylation driver genes for HCC extrahepatic metastasis, of which two genes (DHX58 and EIF5A2) were associated with HCC patient prognosis. And the study further constructed and validated the risk score and prognostic model. Immunoinfiltration analysis showed that M0 macrophage abundance was correlated with the prognosis of HCC patients. Immunohistochemistry revealed differences in DHX58 and EIF5A2 expression between HCC tissues with and without extrahepatic metastasis, consistent with our bioinformatics findings.

The regucalcin gene is located on the X chromosome, comprising seven exons and six introns. This gene and protein are expressed in various tissues and cells and is predominantly expressed in human liver, kidney, and adrenal tissues. Regucalcin gene expression is enhanced via a mechanism mediated by several signaling molecules and transcription factors. Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis. In addition, regucalcin has been implicated in several metabolic disorders and diseases. In particular, regucalcin plays a role as a novel suppressor in several types of cancer patients. Increased expression of regucalcin suppresses the growth of human cancer cells, suggesting its pivotal role in suppressing tumor development. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The adhesion, migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, promoting dormancy in cancer patients. Interestingly, regucalcin is also found in human serum, suggesting its character as a novel biomarker in various diseases. This extracellular regucalcin has been shown to suppress human cancer cells' growth and bone metastatic activity. Thus, extracellular regucalcin may play a vital role as a suppressor of human cancer activity. Alteration of the serum regucalcin levels in physiological and pathophysiological conditions may influence the activity of cancer cells in the microenvironment. This review will discuss the potential role of extracellular regucalcin in cancer cell activity as a critical suppressor in the cancer microenvironment.

Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity.

The objective of this study was to investigate the role of circular RNA 0102231 (hsa_circ_ 0102231) in the progression of liver cancer.

In this study, quantitative polymerase chain reaction experiments were performed to quantify the hsa_circ_0102231 level in different liver cancer cell lines. Bioinformatics analysis, as well as a dual-luciferase reporter and RNA pull-down assay, were used to identify putative hsa_circ_ 0102231 downstream targets. Colony formation and CCK8 assays were utilized to examine cell proliferation, whereas Transwell assays were employed to monitor cell migration. Lastly, the role of hsa_circ_0102231 in liver cancer was assessed in a subcutaneous xenograft model.

The expression of hsa_circ_0102231 increased significantly in HepG2 and Huh-7 cells compared with controls, and hsa_circ_0102231 knockdown inhibited cell proliferation and migration in vitro and in vivo. Bioinformatics analysis, as well as a dual-luciferase reporter and RNA pulldown assay, revealed that miR-873 and SOX4 were hsa_circ_0102231 downstream targets. miR-873 inhibition or SOX4 overexpression rescued the proliferation and migration of HepG2 and Huh-7 cells after hsa_circ_0102231 knockdown. Furthermore, SOX4 overexpression reversed the miR-873-induced inhibition of cell migration and proliferation in vitro.

These results show that hsa_circ_0102231 knockdown impedes the progression of liver cancer by regulating the miR-873/SOX4 axis. However, further studies are needed to determine whether hsa_circ_0102231 may be a therapeutic target in liver cancer.

Added safety measures coupled with the development and use of pathogen reduction technologies (PRT) significantly reduces the risk of transfusion-transmitted infections (TTIs) from blood products. Current approved PRTs utilize chemical and/or UV-light based inactivation methods. While the effectiveness of these PRTs in reducing pathogens are well documented, these can cause tolerable yet unintended consequences on the quality and efficacy of the transfusion products. As an alternative to UV-based approaches, we have previously demonstrated that 405 nm violet-blue light exposure successfully inactivates a variety of pathogens, including bacteria, parasites, and viruses, in both platelet concentrates (PCs) and plasma. Herein, we show that 405 nm light treatment effectively inactivates hepatitis C cell culture virus (HCVcc) by up to ~ 3.8 log10 in small volumes of a variety of matrices, such as cell culture media, PBS, plasma, and PCs with 27 J/cm2 of light exposure, and total inactivation of HCVcc after 162 J/cm2 light exposure. Furthermore, we demonstrate that carry-over of media supplemented with fetal bovine serum enhances the production of reactive oxygen species (ROS), providing mechanistic insights to 405 nm light-mediated viral inactivation. Overall, 405 nm light successfully inactivates HCVcc, further strengthening this method as a novel PRT for platelets and plasma.

Ginsenoside Rg3 is an extract from ginseng and has the activities of antitumor in a variety of carcinomas, making it a promising monomer of Chinese herbal medicine for tumor treatment. This study aimed to investigate the targets and mechanisms of action of Rg3 in hepatocellular carcinoma (HCC). The molecular structure of Rg3 was obtained, and 100 potential targets were identified using the SwissTargetPrediction database. Univariate Cox regression analysis on the TCGA-LIHC cohort identified 25 genes as candidate targets of Rg3 with significant prognostic relevance. Consensus clustering divided the TCGA-LIHC cohort into two subtypes: C1 and C2. The C2 subtype exhibited worse overall survival, and significant differences in the expression patterns of the 25 candidate genes were observed between the subtypes. Clinical characteristics also differed significantly between the C1 and C2 subtypes. Mutation analysis showed a higher mutation rate and specific gene mutations in the C2 subtype. Increased immune cell infiltration, including macrophages, Th1 cells, and Th17 cells, was observed in the C2 subtype. Here, an orthotopic murine HCC model was established using Hepa1-6 (murine liver carcinoma cells) in immunocompetent C57BL/6 mice. Rg3 was administered via intraperitoneal injection. Tumor volumes were measured using calipers, and the volume was calculated using the formula: width^2 × length × 0.5. This method, while traditional, has been validated and provides consistent and reliable data for assessing tumor progression and treatment efficacy. The function of Rg3on tumor growth and angiogenesis was evaluated in vitro and in vivo. Especially the role of Rg3 in regulating the myeloid-derived suppressor cells (MDSCs) recruitment and Kupffer cells function were investigated. In the present study we found that Rg3 administration suppressed tumor growth and angiogenesis in vivo. In the liver tissues of HCC-bearing mice, Kupffer cells expressed more co-inhibitory molecule CD274 and less co-stimulatory molecules CD86 and MHCII, whereas Rg3 treatment induced the restoration of Kupffer cells function. Rg3 also increased the efficiency of Kupffer cells as antigen-presenting cells. Furthermore, an increased MDSCs proportion in tumor tissues and surrounding parenchyma was detected in HCC-bearing livers, and this enhancement was blocked after Rg3 administration. In vitro, co-culture of Kupffer cells with MDSCs resulted in decreased CD86 expression and increased CD274 expression in Kupffer cells. Kupffer cells also produced decreased IL-6 and IL-18 level and upregulated IL-10 level after co-culture with MDSCs. This study provides insights into the potential targets and mechanisms of Rg3 in HCC and lays a foundation for personalized treatment strategies.

The onset of metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC) is insidious and exhibits sex-specific variations. Effective methods for monitoring MASLD-HCC progression in females have not yet been developed.

Transcriptomic data of female liver tissue samples were obtained from multiple public databases. Differentially expressed genes (DEGs) in MASLD-HCC were identified using differential expression and robust rank aggregation analyses. Diagnostic prediction models for MASLD (DP.MASLD) and HCC (DP.HCC) were developed and validated using elastic net analysis, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Bioinformatics was used to assess the pathogenesis of MASLD-HCC.

Seven overlapping DEGs were identified in female patients with MASLD and HCC: AKR1B10, CLEC1B, CYP2C19, FREM2, MT1H, NRG1, and THBS1). The area under the ROC curve (AUC) values for the training and validation groups of the DP.MASLD model were 0.864 and 0.782, 0.932 and 1.000, and 0.920 and 0.969 when differentiating between the steatosis and normal liver, steatohepatitis and steatosis, and steatohepatitis and normal liver groups, respectively. The AUCs for DP.HCC were 0.980 and 0.997 in the training and validation groups, respectively. The oncogenesis of female MASLD-HCC is associated with molecular pathways, including cytochrome P450-associated drug metabolism, tyrosine metabolism, fatty acid degradation, focal adhesion, extracellular matrix receptor interactions, and protein digestion and absorption.

A novel and effective method to quantitatively assess the risk of MASLD-HCC progression in female patients was developed, and this method will aid in the generation of precise diagnostic, preventive, and therapeutic strategies.

The prognostic impact of preoperative gamma-glutamyl transpeptidase to platelet ratio (GPR) levels in patients with solitary hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) following radical resection has not been established.

To examine the clinical utility of GPR for prognosis prediction in solitary HBV-related HCC patients.

A total of 1167 solitary HBV-related HCC patients were retrospectively analyzed. GPR levels were compared with 908 non-HCC individuals. Overall survival (OS) and recurrence-free survival (RFS) were evaluated, and cox proportional hazard model analyses were performed to identify independent risk factors. Differences in characteristics were adjusted by propensity score matching (PSM). Subgroup and stratified survival analyses for HCC risks were performed, and a linear trend of the hazard ratio (HR) according to GPR levels was constructed.

GPR levels of patients with solitary HBV-related HCC were higher than those with hepatic hemangiomas, chronic hepatitis B and healthy control (adjusted P < 0.05). Variable bias was diminished after the PSM balance test. The low GPR group had improved OS (P < 0.001) and RFS (P < 0.001) in the PSM analysis and when combined with other variables. Multivariate cox analyses suggested that low GPR levels were associated with a better OS (HR = 0.5, 95%CI: 0.36-0.7, P < 0.001) and RFS (HR = 0.57, 95%CI: 0.44-0.73, P < 0.001). This same trend was confirmed in subgroup analyses. Prognostic nomograms were constructed and the calibration curves showed that GPR had good survival prediction. Moreover, stratified survival analyses found that GPR > 0.6 was associated with a worse OS and higher recurrence rate (P for trend < 0.001).

Preoperative GPR can serve as a noninvasive indicator to predict the prognosis of patients with solitary HBV-related HCC.

In 2017, the American College of Radiology introduced the US Liver Imaging Reporting and Data System (LI-RADS) as a framework for US surveillance of patients at risk for developing hepatocellular carcinoma. This has aided in the standardization of technique, clinical reporting, patient management, data collection, and research. Emerging evidence has helped inform changes to the algorithm, now released as LI-RADS US Surveillance version 2024. The updated algorithm, the rationale for changes, and its alignment with the 2023 American Association for the Study of Liver Diseases Practice Guidance are presented.

Resistance to immune checkpoint inhibitors (ICIs) significantly limits the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC). However, the mechanisms underlying immunotherapy resistance remain poorly understood. Our aim was to clarify the role of membrane-associated ring-CH-type finger 3 (MARCHF3) in HCC within the framework of anti-programmed cell death protein-1 (PD-1) therapy.

MARCHF3 was identified in the transcriptomic profiles of HCC tumors exhibiting different responses to ICIs. In humans, the correlation between MARCHF3 expression and the tumor microenvironment (TME) was assessed via multiplex immunohistochemistry. In addition, MARCHF3 expression in tumor cells and immune cell infiltration were assessed by flow cytometry.

MARCHF3 was significantly upregulated in tumors from patients who responded to ICIs. Increased MARCHF3 expression in HCC cells promoted dendritic cell (DC) maturation and stimulated CD8+ T-cell activation, thereby augmenting tumor control. Mechanistically, we identified MARCHF3 as a pivotal regulator of the DNA damage response. It directly interacted with Poly(ADP-Ribose) Polymerase 1 (PARP1) via K48-linked ubiquitination, leading to PARP1 degradation. This process promoted the release of double-strand DNA and activated cCAS-STING in DCs, thereby initiating DC-mediated antigen cross-presentation and CD8+ T-cell activation. Additionally, ATF4 transcriptionally regulated MARCHF3 expression. Notably, the PARP1 inhibitor olaparib augmented the efficacy of anti-PD-1 immunotherapy in both subcutaneous and orthotopic HCC mouse models.

MARCHF3 has emerged as a pivotal regulator of the immune landscape in the HCC TME and is a potent predictive biomarker for HCC. Combining interventions targeting the DNA damage response with ICIs is a promising treatment strategy for HCC.

To systematically evaluate the efficacy of arterial compression hemostasis devices after femoral artery puncture interventions for hepatocellular carcinoma (HCC).

We systematically searched 10 electronic databases (PubMed, Scopus, EMBASE, The Cochrane Library, CINAHL, Web of Science, CNKI, Wanfang, VIP, and CBM) up to October 20, 2024, to identify randomized controlled trials (RCTs) of arterial compression hemostasis devices used after HCC interventions through femoral artery puncture. We used the Cochrane risk of bias assessment tool to evaluate the trial quality, and we analyzed the data with Review Manager 5.4 software.

17 RCTs involving 2,338 participants met the inclusion criteria. The meta-analysis demonstrated that, compared with conventional manual compression combined with sandbags, the use of arterial compression hemostasis devices significantly shortened the compression hemostasis time [MD = -13.9 min, 95% CI, -14.19 to -12.19; P < 0.00001] and limb immobilization time [MD = -8.79 min, 95% CI, -12.65 to -4.94; P < 0.00001]. Additionally, it significantly reduced the incidence of local bleeding [RR = 0.28, 95% CI, 0.20 to 0.40; P < 0.00001], hematoma formation [RR = 0.29, 95% CI, 0.18 to 0.46; P < 0.00001], skin ecchymosis [RR = 0.25, 95% CI, 0.18 to 0.35; P < 0.00001], dysuria [RR = 0.22, 95% CI, 0.14 to 0.34; P = 0.0002], skin damage [RR = 0.16, 95% CI, 0.05 to 0.54; P = 0.003], backache [RR = 0.28, 95% CI, 0.13 to 0.64; P = 0.002], and pseudoaneurysm [RR = 0.22, 95% CI, 0.10 to 0.51; P = 0.0004].

The analysis revealed that arterial compression hemostasis devices significantly reduce hemostasis and immobilization time, as well as vascular complications in liver cancer patients undergoing interventional therapy.

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. Affected patients have poor prognoses due to high rates of post-surgical recurrence and metastasis. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) reportedly contributes to the development and progression of various human cancers. Thus far, there have been no comprehensive studies regarding the expression of BAMBI in HCC; similarly, no studies have investigated the prognostic significance of BAMBI and its associated mechanisms in HCC. In this study, we analyzed the expression profiles of BAMBI, along with its contributions to pathological findings, metastasis characteristics, and prognosis, in multiple human cancers. We found that upregulation of BAMBI was associated with poor prognosis in HCC. Next, we explored the associations of BAMBI with multiple cell signaling pathways, immune cells, and immune checkpoints in HCC. The results showed that BAMBI was associated with tumor proliferation, epithelial-mesenchymal transition (EMT) markers, glycolysis, fatty acid biosynthesis and degradation pathways, and immune checkpoint regulation in HCC. In vitro and in vivo experiments showed that BAMBI promoted polarization of M1 macrophages and is linked to the expression of key genes involved in glycolipid metabolism. Furthermore, protein-protein interaction analysis suggested that BAMBI plays multiple roles in HCC by regulating genes in the transforming growth factor (TGF)-β and Wnt signaling pathways. Our findings elucidated that BAMBI is a prognostic biomarker and is associated with macrophage polarization, glycolysis, and lipid metabolism in HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and the development of effective treatment strategies remains a significant challenge in the management of advanced HCC patients. The emergence of tyrosine kinase inhibitors (TKIs) has been a significant advancement in the treatment of HCC, as these targeted therapies have shown promise in prolonging the survival of patients with advanced disease. Although immunotherapy is currently considered as the first line of treatment for advanced HCC patients, many such patients do not meet the clinical criteria to be eligible for immunotherapy, and in many parts of the world there is still lack of accessibility to immunotherapy. As such, TKIs still serve as the first line of treatment and play a major role in the treatment repertoire for advanced HCC patients. However, the development of resistance to these agents is a major obstacle that must be overcome. In this review, we explore the underlying mechanisms of resistance to TKIs in HCC, the clinical implications of this resistance, and the potential strategies to overcome or prevent the emergence of resistance.

Prognosticating survival among patients with HCC and cirrhosis must account for both the tumor burden/stage, as well as the severity of the underlying liver disease. Although there are many staging systems used to guide therapy, they have not been widely adopted to predict patient-level survival after the diagnosis of HCC. We sought to develop a score to predict long-term survival among patients with early- to intermediate-stage HCC using purely objective criteria.

Retrospective cohort study among patients with HCC confined to the liver, without major medical comorbidities within the Veterans Health Administration from 2014 to 2023. Tumor data were manually abstracted and combined with clinical and laboratory data to predict 5-year survival from HCC diagnosis using accelerated failure time models. The data were randomly split using a 75:25 ratio for training and validation. Model discrimination and calibration were assessed and compared to other HCC staging systems.

The cohort included 1325 patients with confirmed HCC. A risk score using baseline clinical, laboratory, and HCC-related survival had excellent discrimination (integrated AUC: 0.71 in the validation set) and calibration (based on calibration plots and Brier scores). Models had superior performance to the BCLC and ALBI scores and similar performance to the combined BCLC-ALBI score.

We developed a risk score using purely objective data to accurately predict long-term survival for patients with HCC. This score, if validated, can be used to prognosticate survival for patients with HCC, and, in the setting of liver transplantation, can be incorporated to consider the net survival benefit of liver transplantation versus other curative options.

The interactions between cancer cells and tumor-associated macrophages (TAMs) via microRNAs (miRNAs) play crucial roles in malignant potential and drug resistance. However, it remains unclear how lenvatinib-resistant hepatocellular carcinoma (LR HCC) promotes TAM tumor biology. Here we investigated the crosstalk between LR HCC cells and TAMs for cancer progression and lenvatinib resistance, focusing on an exosomal miRNA.

We used two bioinformatics software programs to identify miRNAs that target PTEN in gastrointestinal cancers, then investigated exosomal miRNA expression in LR HCC conditioned medium (CM). After modifying TAMs with LR HCC CM (LR TAM), macrophage phenotype and PTEN-Nrf2 signaling pathway component expression were analyzed in LR TAMs. The malignant potential and drug resistance were investigated in naïve HCC cells cultured with LR TAM CM.

LR HCC cells highly induced M2-like properties in macrophages compared with naïve HCC cells. Exosomal miR-301a-3p expression was increased in LR HCC CM, with higher activation of the PTEN/PI3K/GSK3β/Nrf2 signaling pathway in LR TAMs. Naïve HCC cells were educated with LR TAM CM to promote malignant potential and lenvatinib resistance. Inhibition of exosomal miR-301a-3p prevented the malignant potential of LR TAMs. Activation of Nrf2 signaling by LR HCC cell-derived exosomal miR-301a-3p skewed the transformation of macrophages to the M2 phenotype.

Our study provides new findings on the role of miR-301a-3p, suggesting it is a promising therapeutic target to improve HCC lenvatinib resistance.

Retrospective cohort study.

Spinal metastasis from hepatocellular carcinoma is rapidly progressive and predisposes to spinal disability, cord compression and further neural injury, leading to poor prognosis. Currently, it is still challenging to look for a treatment strategy that can improve the quality of life of patients and even directly prolong the survival time. This study attempts to evaluate the clinical efficacy of separation operation combined with postoperative stereotactic radiotherapy (SRT/SRS) in the treatment of hepatocellular carcinoma patients developing spinal metastasis and epidural spinal cord compression.

Patients with metastases spinal cord compression from hepatocellular carcinoma were studied retrospectively and divided into two groups, the SO group (who undergo separation operations combined with postoperative SRS, n = 32) and RT group (who received only SRS, n = 28). The visual Analogue Scale (VAS) pain score, Frankel grade, Karnofsky performance score, and Quality of Life (SF-36) score were comparatively analyzed between the two groups.

Significantly higher VAS pain scores, Frankel grades, Karnofsky performance scores and Quality of Life (SF-36) scores were demonstrated in patients with combination treatment than in patients with SRS alone.

Separation operations are effective surgical procedure for the treatment of spinal metastatic tumor from hepatocellular carcinoma with spinal cord compression. The combination with postoperative SRS can significantly improve the quality of life in this patient population via spinal canal decompression and spinal stability reconstruction.

Globally, hormone-responsive cancers afflict millions of people contributing to cancer-related morbidity and mortality. While hormone-responsive cancers overburden patients, their close families, and even health budgets at the local levels, knowledge of these cancers particularly their biology and possible avenues for therapy remains poorly exploited. Herewith, this review highlights the role of sex hormones (estrogens and androgens) in the pathophysiology of hormone-responsive cancers and the exploration of therapeutic targets. Major scientific databases including but not limited to Scopus, PubMed, Science Direct, Web of Science core collections, and Google Scholar were perused using a string of search terms: Hormone-responsive cancers, androgens and cancers, estrogens and cancer, androgen receptor signalling, estrogen receptor signalling, etc.

The circadian system plays a crucial role in regulating metabolic homeostasis at both systemic and tissue levels by synchronizing the central and peripheral clocks with exogenous time cues, known as zeitgebers (such as the light/dark cycle). Our body's behavioral rhythms, including sleep-wake cycles and feeding-fasting patterns, align with these extrinsic time cues. The body cannot effectively rest and repair itself when circadian rhythms are frequently disrupted. In many shift workers, the internal rhythms fail to fully synchronize with the end and start times of their shifts. Additionally, exposure to artificial light at night (LAN), irregular eating patterns, and sleep deprivation contribute to circadian disruption and misalignment. Shift work and jet lag disrupt the normal circadian rhythm of liver activity, resulting in a condition known as "circadian disruption". This disturbance adversely affects the metabolism and homeostasis of the liver, contributing to excessive fat accumulation and abnormal liver function. Additionally, extended working hours, such as prolonged night shifts, may worsen the progression of non-alcoholic fatty liver disease (NAFLD) toward non-alcoholic steatohepatitis (NASH) and increase disease severity. Studies have demonstrated a positive correlation between night shift work (NSW) and elevated liver enzymes, indicative of hepatic metabolic dysfunction, potentially increasing the risk of hepatocellular carcinoma (HCC) related to NAFLD. This review consolidates research findings on circadian disruption caused by NSW, late chronotype, jet lag, and social jet lag, drawing insights from studies involving both humans and animal models that investigate the effects of these factors on circadian rhythms in liver metabolism.