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Xiao Y, He M, Zhang X, Yang M, Yuan Z, Yao S, Qin Y. Research progress on the mechanism of tumor cell ferroptosis regulation by epigenetics. Epigenetics 2025; 20:2500949. [PMID: 40327848 PMCID: PMC12064064 DOI: 10.1080/15592294.2025.2500949] [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: 02/14/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/08/2025] Open
Abstract
Cancer remains a significant barrier to human longevity and a leading cause of mortality worldwide. Despite advancements in cancer therapies, challenges such as cellular toxicity and drug resistance to chemotherapy persist. Regulated cell death (RCD), once regarded as a passive process, is now recognized as a programmed mechanism with distinct biochemical and morphological characteristics, thereby presenting new therapeutic opportunities. Ferroptosis, a novel form of RCD characterized by iron-dependent lipid peroxidation and unique mitochondrial damage, differs from apoptosis, autophagy, and necroptosis. It is driven by reactive oxygen species (ROS)-induced lipid peroxidation and is implicated in tumorigenesis, anti-tumor immunity, and resistance, particularly in tumors undergoing epithelial-mesenchymal transition. Moreover, ferroptosis is associated with ischemic organ damage, degenerative diseases, and aging, regulated by various cellular metabolic processes, including redox balance, iron metabolism, and amino acid, lipid, and glucose metabolism. This review focuses on the role of epigenetic factors in tumor ferroptosis, exploring their mechanisms and potential applications in cancer therapy. It synthesizes current knowledge to provide a comprehensive understanding of epigenetic regulation in tumor cell ferroptosis, offering insights for future research and clinical applications.
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Affiliation(s)
- Yuyang Xiao
- Department of Health Management Medical, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Mengyang He
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xupeng Zhang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Meng Yang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Zhangchi Yuan
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Shanhu Yao
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan, China
| | - Yuexiang Qin
- Department of Health Management Medical, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Xie J, Liu W, Deng X, Wang H, Ou X, An X, Situ MY, Yang A, Peng C, He R, Xie Y, Tang H, Chen Y, Liang JY, Shao R, Xiao W, Zheng S. Paracrine Orchestration of Tumor Microenvironment Remodeling Induced by GLO1 Potentiates Lymph Node Metastasis in Breast Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e00722. [PMID: 40492378 DOI: 10.1002/advs.202500722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 04/24/2025] [Indexed: 06/12/2025]
Abstract
Breast cancer is the most prevalent form of malignant tumor that frequently metastasizes to axillary lymph nodes (LNs). Nonetheless, the precise mechanisms underlying alterations in the tumor microenvironment (TME) in LN metastasis in breast cancer remain poorly understood. Single-cell RNA sequencing of 28 LN samples from 23 patients is performed, and a comprehensive landscape of the entire ecosystem is generated. Ten major cell types are identified, with the subclusters of each major cell type exhibiting diverse characteristics. Furthermore, multiple signatures are collected to evaluate the key components of the subclusters using multi-omics methodologies. This study finds that myCAFs may hasten LN metastasis, and observed a notable increase in APOE+ macrophages and a higher proportion of exhausted CD8+ T cells, contributing to the immunosuppressive TME. Moreover, cancer cells in metastatic lesions exhibited diverse expression patterns linked to proliferation, metastasis, oxidative phosphorylation, hypoxia, and interferon responses. Using multi-omics approaches and experimental validations, it determines that GLO1 can promote lymphatic angiogenesis, metastasis, and inhibit the proteasomal degradation of GSS, thereby maintaining intracellular glutathione (GSH) and reactive oxygen species (ROS) balance. Collectively, the study offers novel perspectives on the microenvironment remodeling of breast cancer LN metastases, suggesting that GLO1 may be a promising therapeutic target.
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Affiliation(s)
- Jindong Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Wenjian Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xinpei Deng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Huan Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xueqi Ou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xin An
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Min-Yi Situ
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Anli Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Chuan Peng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Rongfang He
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Yi Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yuman Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Jie-Ying Liang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ruonan Shao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Weikai Xiao
- Department of Breast Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Shaoquan Zheng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
- Department of Breast Surgery, Breast Disease Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Li MH, Yang Y, Dong QQ, Tao H, Lu C, Yang JJ. Novel epitranscriptomic and epigenetic therapeutic strategies and targets for ferroptosis in liver fibrosis. Eur J Pharmacol 2025; 996:177344. [PMID: 40015597 DOI: 10.1016/j.ejphar.2025.177344] [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: 11/17/2024] [Revised: 01/23/2025] [Accepted: 01/31/2025] [Indexed: 03/01/2025]
Abstract
Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) and the activation of hepatic stellate cells (HSCs), which are influenced by epitranscriptomic and epigenetic factors. Recent advancements in epigenetic and epitranscriptomic research have revealed new opportunities for therapeutic interventions, particularly through the regulation of ferroptosis, a type of programmed cell death that is specifically linked to iron-dependent lipid peroxidation. In the context of liver fibrosis, a progressive scarring process that can progress to cirrhosis and ultimately end-stage liver disease, targeting these regulatory mechanisms to modulate ferroptosis presents a promising therapeutic strategy. This review aims to consolidate current knowledge on the epigenetic and epitranscriptomic control of ferroptosis and investigate its potential implications for the treatment of liver fibrosis.
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Affiliation(s)
- Ming-Hui Li
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China; School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Center for Scientific Research and Experiment, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Yang Yang
- Department of General Surgery, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, 215153, China
| | - Qi-Qi Dong
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China; School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Center for Scientific Research and Experiment, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Hui Tao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China; Center for Scientific Research and Experiment, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
| | - Chao Lu
- First Affiliated Hospital, Anhui University of Science & Technology, Huainan, 232001, China.
| | - Jing-Jing Yang
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China; Center for Scientific Research and Experiment, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
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Jawed R, Bhatti H, Khan A. Genetic profile of ferroptosis in non-small cell lung carcinoma and pharmaceutical options for ferroptosis induction. Clin Transl Oncol 2025; 27:1867-1886. [PMID: 39460894 DOI: 10.1007/s12094-024-03754-4] [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: 04/23/2024] [Accepted: 10/04/2024] [Indexed: 10/28/2024]
Abstract
Lung cancer (LC) is the leading cause of cancer-related deaths and the second most commonly diagnosed malignancy worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell LC (LUSCC) are the most common subtypes of non-small cell LC (NSCLC). Early diagnosis of LC can be challenging due to a lack of biomarkers. The overall survival (OS) of patients with NSCLC is still poor despite the enormous efforts that have been made to develop novel treatments. Understanding fundamental molecular and genetic mechanisms is necessary to develop new therapeutic approaches for NSCLC. A recently identified type of programmed cell death known as ferroptosis is one potential approach. Ferroptosis causes oxidative damage and the death of cancerous cells by peroxidizing unsaturated phospholipids and accumulating reactive oxygen species (ROS) in an iron-dependent manner. Ferroptosis-related gene (FRG) signatures have recently been evaluated for their ability to predict patient OS and prognosis. These analyses show FRGs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Moreover, we summarize the current pharmaceutical options of ferroptosis induction and their underlying molecular mechanism in LC. Therefore, this review aims to provide a comprehensive summary of FRG-based prognostic models, their associated metabolic and signaling pathways, and promising therapeutic options for ferroptosis induction in NSCLC.
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Affiliation(s)
- Rohil Jawed
- Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing, 210023, China.
| | - Huma Bhatti
- School of Chemistry and Chemical Engineering, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, 210023, China
| | - Adnan Khan
- Clinical and Molecular Labs, Karachi Institute of Radiotherapy and Nuclear Medicine (KIRAN), KDA Scheme 33 Near Safoora Chowk, Karachi, Pakistan
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Liu X, Shen F, Wang T, Li J, Sheng X, Deng Y, Zhang X, Zhao B, Zhou Y, Shang P, Shi X, Zhao Z, Yu Z, Mukherjee S, Saeed A, Liu J. Construction of a multigenic diagnostic, prognostic, and immune infiltration model with methylation-associated regulators in esophageal squamous cell carcinoma. J Thorac Dis 2025; 17:2605-2622. [PMID: 40400969 PMCID: PMC12090105 DOI: 10.21037/jtd-2025-341] [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: 02/18/2025] [Accepted: 03/28/2025] [Indexed: 05/23/2025]
Abstract
Background Methylation-related regulators may be involved in the prognostic prediction of esophageal squamous cell carcinoma (ESCC). Our study aimed to apply bioinformatics to screen methylation-related regulators for the construction of a prognostic model for patients with ESCC and to assess their diagnostic value and correlation with immune infiltration. Methods Prognosis-related genes were identified from The Cancer Genome Atlas (TCGA) database. Methylation-associated genes were filtered using the GeneCards database. We used the least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression to identify the prognostic indicators. We applied the single-sample gene set enrichment analysis (ssGSEA) to clarify the relationship between prognostic indicators and immune infiltration in patients with ESCC (n=82). Results We constructed a prognostic model using methylation-related regulators homocysteine-inducible ER protein with ubiquitin-like domain 1 (HERPUD1), trans-2,3-enoyl-CoA reductase (TECR), melanoma antigen gene A11 (MAGEA11), and NOP2/Sun RNA methyltransferase 6 (NSUN6) to evaluate the prognosis of patients with ESCC. A higher prognostic risk score was associated with shorter overall survival (OS) in patients with ESCC [hazard ratio (HR) =5.77, 95% confidence interval (CI): 2.13-15.58; P<0.001]. Time-dependent area under the curve (AUC) analysis revealed that HERPUD1, TECR, MAGEA11, and NSUN6 had high prognostic predictive value at different time points. Furthermore, we found that the combined diagnostic model based on HERPUD1, TECR, MAGEA11, and NSUN6 had excellent diagnostic efficacy for ESCC (AUC =0.911; 95% CI: 0.888-0.935). Finally, the ssGSEA algorithm showed that HERPUD1 was significantly positively correlated with immune infiltration at both the cellular and genetic levels, while TECR showed a significant negative correlation with immune infiltration levels. Conclusions Our prognostic model, built with the methylation-related regulators HERPUD1, TECR, MAGEA11, and NSUN6, could effectively predict prognosis in patients with ESCC, enhance diagnostic efficacy, and reflect immune cell infiltration in their microenvironment. Our findings are hypothesis generating and larger confirmatory studies are needed to validate our results.
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Affiliation(s)
- Xing Liu
- Department of Oncology, Ankang Central Hospital, Ankang, China
| | - Feng Shen
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Ting Wang
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Jingru Li
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Xiaowei Sheng
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Yulan Deng
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Xuewei Zhang
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Bing Zhao
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Ying Zhou
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Peng Shang
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Xinyi Shi
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
| | - Zilong Zhao
- Department of Pathology, Ankang Central Hospital, Ankang, China
| | - Zhonglin Yu
- Department of Thoracic Surgery, Ankang Central Hospital, Ankang, China
| | - Sarbajit Mukherjee
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Anwaar Saeed
- Division of Hematology & Oncology, Department of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Jing Liu
- Department of Clinical Laboratory, Ankang Central Hospital, Ankang, China
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Jiang X, Huang Y, Hong X, Wu W, Lin Y, Lin L, Xue Y, Lin D. Exogenous dihomo-γ-linolenic acid triggers ferroptosis via ACSL4-mediated lipid metabolic reprogramming in acute myeloid leukemia cells. Transl Oncol 2025; 52:102227. [PMID: 39644823 PMCID: PMC11667188 DOI: 10.1016/j.tranon.2024.102227] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/24/2024] [Accepted: 11/28/2024] [Indexed: 12/09/2024] Open
Abstract
Ferroptosis is a novel type of programmed cell death caused by excessive iron-dependent lipid peroxidation. According to various studies, there may be a link between ferroptosis and lipid metabolism. However, few studies have been reported on the lipid metabolism of ferroptosis in acute myeloid leukemia (AML). Here, we analyzed the relationship between lipid metabolism and ferroptosis in AML cells to explore new clinical treatment strategies. This study found that 12 fatty acids were significantly changed in acute myeloid leukemia cell ferroptosis, including dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA), etc. Exogenous DGLA substantially increases the sensitivity to ferroptosis and induces ferroptosis alone in AML cells. In addition, acyl-CoA synthetase long-chain family member 4 (ACSL4) knockout significantly inhibited DGLA-induced AML cells ferroptosis, and ACSL4 regulates DGLA-associated lipid synthesis to affect the sensitivity of AML cells to ferroptosis. Collectively, our studies indicate that a DGLA-enriched diet significantly restricted the growth of leukemia cells as well as induced ferroptosis in vivo.
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Affiliation(s)
- Xiandong Jiang
- Department of Laboratory Medicine, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China
| | - Yingying Huang
- Department of Laboratory Medicine, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China
| | - Xiaoying Hong
- Department of Laboratory Medicine, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China
| | - Wei Wu
- Department of Laboratory Medicine, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Medical Technology Experimental Teaching Center, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China
| | - Yanfeng Lin
- Medical Technology Experimental Teaching Center, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China
| | - Liping Lin
- Department of Laboratory Medicine, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China
| | - Yan Xue
- Medical Technology Experimental Teaching Center, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China.
| | - Donghong Lin
- Department of Laboratory Medicine, The School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou 350122, China.
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Yang Z, Zhang T, Zhu X, Zhang X. Ferroptosis-Related Transcriptional Level Changes and the Role of CIRBP in Glioblastoma Cells Ferroptosis. Biomedicines 2024; 13:41. [PMID: 39857625 PMCID: PMC11761263 DOI: 10.3390/biomedicines13010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/24/2024] [Accepted: 12/25/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVE We aimed to elucidate the roles of ferroptosis-associated differentially expressed genes (DEGs) in glioblastoma and provide a comprehensive resource for researchers in the field of glioblastoma cell ferroptosis. METHODS We used RNA sequencing to identify the DEGs associated with erastin-induced ferroptosis in glioblastoma cells. We further unraveled the biological functions and clinical implications of cold-inducible RNA-binding protein (CIRBP) in the context of glioblastoma by using a multifaceted approach, encompassing gene expression profiling, survival analysis, and functional assays to elucidate its role in glioblastoma cell mortality and its potential influence on patient prognosis. RESULTS We identified and validated the gene encoding CIRBP, the expression of which is altered during glioblastoma ferroptosis. Our findings highlight the relationship between CIRBP expression and ferroptosis in glioblastoma cells. We demonstrated that CIRBP modulates key aspects of cell death, thereby altering the sensitivity of glioblastoma cells to erastin-induced ferroptosis. A prognostic model, constructed based on CIRBP expression levels, revealed an association between lower CIRBP levels and poorer prognosis in glioma patients; this finding was corroborated by our comprehensive in vitro and in vivo assays that highlighted the impact of modulating CIRBP expression on glioblastoma cell viability and ferroptotic response. CONCLUSION Our research unravels the complex molecular dynamics of ferroptosis in glioblastoma and underscores CIRBP as a potential biomarker and therapeutic target. This improved understanding of the role of CIRBP in ferroptosis paves the way for more precise and efficacious treatments for glioblastoma, potentially improving patient outcomes.
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Affiliation(s)
- Zijiang Yang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
| | - Ting Zhang
- Department of Central Laboratory, Jiangyin Clinical College of Xuzhou Medical University, Jiangyin 214400, China;
| | - Xuanlin Zhu
- School of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai 200433, China;
| | - Xiaobiao Zhang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Digital Medical Research Center, Fudan University, Shanghai 200032, China
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Ma C, Gao L, Song K, Gu B, Wang B, Pu W, Chen H. Exploring the therapeutic potential of diterpenes in gastric cancer: Mechanisms, efficacy, and clinical prospects. BIOMOLECULES & BIOMEDICINE 2024; 25:1-15. [PMID: 39151097 PMCID: PMC11647260 DOI: 10.17305/bb.2024.10887] [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: 06/26/2024] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 08/18/2024]
Abstract
Gastric cancer (GC) remains a significant global health challenge, particularly prevalent in East Asia. Despite advancements in various treatment modalities, the prognosis for patients, especially those in advanced stages, remains poor, highlighting the need for innovative therapeutic approaches. This review explores the promising potential of diterpenes, naturally occurring compounds with robust anticancer properties, derived from diverse sources such as plants, marine organisms, and fungi. Diterpenes have shown the ability to influence reactive oxygen species (ROS) generation, ferroptosis, and autophagy, positioning them as attractive candidates for novel cancer therapies. This review explores the mechanisms of action of diterpenes and their clinical implications for the treatment of GC. Additionally, it addresses the challenges in translating these compounds from preclinical studies to clinical applications, emphasizing the need for further research to enhance their therapeutic profiles and minimize potential side effects. The discussion underscores the importance of diterpenes in future anticancer strategies, particularly in the fight against gastric cancer.
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Affiliation(s)
- Chenhui Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Lei Gao
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Kewei Song
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Baohong Gu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Bofang Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Weigao Pu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Hao Chen
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, China
- Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, China
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Zhang C, Gao L, Zhang Y, Jin X, Wang M, Wang Q, Zhao W, Wu N, Zhang Y, Liu Y, Zhang Y, Ma L, Chen Y. Corosolic acid inhibits EMT in lung cancer cells by promoting YAP-mediated ferroptosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156110. [PMID: 39369568 DOI: 10.1016/j.phymed.2024.156110] [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: 07/08/2024] [Revised: 09/15/2024] [Accepted: 09/28/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Corosolic acid (CA), a naturally occurring pentacyclic triterpenoid is renowned for its anticancer attributes. Previous studies have predominantly centered on the anticancer properties of CA in lung cancer, specifically its role in inducing apoptosis, however, investigations regarding its involvement in ferroptosis have been scarce. METHODS The apoptotic and proliferative effects were evaluated by CCK8 and colony formation assay. Cell death and ROS generation were measured to assess the response of CA to iron death induction. Scratch and invasion assays were performed to verify the effect of CA on the invasive ability of lung cancer cells. Protein and mRNA expression were analyzed using Western blotting and qPCR. The CHX assay was carried out to detect protein half-life. Metabolite levels were measured with appropriate kits. Protein expression was detected through IF and IHC. A xenograft tumor model was established to investigate the inhibitory effect of CA on lung cancer in vivo. RESULTS The current findings revealed that CA exerts its anticancer effect by inducing cell death, accompanied by the accumulation of lipid reactive oxygen species (ROS), hinting at the possible involvement of ferroptosis. Our experimental results further substantiated the significance of ferroptosis in the CA anticancer mechanism, as ferroptosis inhibitors were found to effectively rescue CA-induced cell death. Significantly, we demonstrated for the first time that CA could induce ferroptosis further by suppressing EMT in lung cancer cells. Additionally, CA could regulate GPX4 to induce ferroptosis, interestingly, CA downregulated GSH synthetase by inhibiting YAP rather than GPX4, thereby reducing GSH, inducing ferroptosis, and further suppressing EMT in lung cancer cells.We also discovered that GSS is a crucial downstream target of YAP in regulating GSH. Moreover, a xenograft mouse model indicated that CA could trigger ferroptosis in lung cancer cells by regulating YAP expression and GSH levels. CONCLUSION CA inhibited lung cancer cell metastasis by inducing ferroptosis. Our data offer the first evidence that CA induces ferroptosis in lung cancer cells by regulating YAP/GSS to modulate GSH, thereby further suppressing EMT. These results imply the potential of CA as an inducer of ferroptosis to inhibit lung cancer metastasis.
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Affiliation(s)
- Congcong Zhang
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Lingli Gao
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Yinghui Zhang
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Xiaoqin Jin
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Mengyu Wang
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China.
| | - Qianna Wang
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Wenyu Zhao
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Nan Wu
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Yasu Zhang
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Yaru Liu
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China
| | - Yanyu Zhang
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China.
| | - Liangliang Ma
- Rehabilitation Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan 450014, PR China.
| | - Yulong Chen
- Rehabilition Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, PR China.
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10
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Ouyang S, Zeng Z, He J, Luo L. Epigenetic regulation of targeted ferroptosis: A new strategy for drug development. J Pharm Anal 2024; 14:101012. [PMID: 39850234 PMCID: PMC11755343 DOI: 10.1016/j.jpha.2024.101012] [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: 01/28/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 01/25/2025] Open
Abstract
Ferroptosis is a newly discovered form of cell death that is influenced by iron levels and is triggered by cellular metabolism and excessive lipid peroxidation. Epigenetic regulation plays a crucial role in the development and progression of diseases, making it essential to understand these mechanisms in order to identify potential targets for drug development and clinical treatment. The intersection of ferroptosis and epigenetics has opened up new avenues for research in drug development, offering innovative strategies for combating diseases. Recent studies have shown that epigenetic modifications can impact pathways related to ferroptosis, potentially leading to organ dysfunction. Despite the increasing focus on this relationship, the role of epigenetic regulation in drug development remains largely unexplored. This article explores current research on the interplay between epigenetic regulation and ferroptosis, delving into their regulatory mechanisms and discussing the effects of existing epigenetic modification regulators on diseases. Additionally, we highlight ongoing research on epigenetic factors involved in targeting ferroptosis in cancer, providing new insights for the development of cancer treatments.
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Affiliation(s)
- Shengli Ouyang
- The First Clinical College, Guangdong Medical University, Zhanjiang, Guangdong, 524023, China
| | - Zeyao Zeng
- The First Clinical College, Guangdong Medical University, Zhanjiang, Guangdong, 524023, China
| | - Jieyi He
- The First Clinical College, Guangdong Medical University, Zhanjiang, Guangdong, 524023, China
| | - Lianxiang Luo
- The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, Guangdong, 524023, China
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11
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Zhang J, Zhao Y, Yan L, Tan M, Jin Y, Yin Y, Han L, Ma X, Li Y, Yang T, Jiang T, Li H. Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway. iScience 2024; 27:110448. [PMID: 39091464 PMCID: PMC11293524 DOI: 10.1016/j.isci.2024.110448] [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: 10/12/2023] [Revised: 01/20/2024] [Accepted: 07/01/2024] [Indexed: 08/04/2024] Open
Abstract
Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, and the restoration of coronary blood flow can also cause heart damage. In this study, we found that corosolic acid (CA), also known as plant insulin, significantly protects the heart from ischemia-reperfusion (I/R) injury. In addition, CA can inhibit oxidative stress and improve mitochondrial structure and function in cardiomyocytes. Subsequently, our study demonstrated that CA improved the expression of the mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), and Parkin. Meanwhile, through molecular docking, we found an excellent binding between CA and PHB2 protein. Finally, the knockdown of PHB2 eliminated the protective effect of CA on hypoxia-reoxygenation in cardiomyocytes. Taken together, our study reveals that CA increases mitophagy in cardiomyocytes via the PHB2/PINK1/Parkin signaling pathway, inhibits oxidative stress response, and maintains mitochondrial function, thereby improving cardiac function after I/R.
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Affiliation(s)
- Jun Zhang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Yongjian Zhao
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Lin Yan
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Mingyue Tan
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Yifeng Jin
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Yunfei Yin
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Lianhua Han
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Xiao Ma
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Yimin Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Tianke Yang
- Department of Ophthalmology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, P.R. China
| | - Tingbo Jiang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
| | - Hongxia Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China
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12
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Zhang J, Zhao Y, Yan L, Tan M, Jin Y, Yin Y, Han L, Ma X, Li Y, Yang T, Jiang T, Li H. Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway. iScience 2024; 27:110448. [DOI: pmid: 39091464 doi: 10.1016/j.isci.2024.110448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2025] Open
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13
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Shu YJ, Lao B, Qiu YY. Research progress of ferroptosis regulating lipid peroxidation and metabolism in occurrence and development of primary liver cancer. World J Gastrointest Oncol 2024; 16:2335-2349. [PMID: 38994128 PMCID: PMC11236230 DOI: 10.4251/wjgo.v16.i6.2335] [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: 12/12/2023] [Revised: 03/06/2024] [Accepted: 04/11/2024] [Indexed: 06/13/2024] Open
Abstract
As a highly aggressive tumor, the pathophysiological mechanism of primary liver cancer has attracted much attention. In recent years, factors such as ferroptosis regulation, lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer, providing a new perspective for understanding the development of liver cancer. Ferroptosis regulation, lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer. The regulation of ferroptosis is involved in apoptosis and necrosis, affecting cell survival and death. Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells. Metabolic abnormalities, especially the disorders of glucose and lipid metabolism, directly affect the proliferation and growth of liver cancer cells. Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes. The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer, and reduce the risk of disease by adjusting the metabolic process. This review focuses on the key roles of ferroptosis regulation, lipid peroxidation and metabolic abnormalities in this process.
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Affiliation(s)
- Yu-Jie Shu
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Bo Lao
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
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14
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Chen J, Ou L, Liu W, Gao F. Exploring the molecular mechanisms of ferroptosis-related genes in periodontitis: a multi-dataset analysis. BMC Oral Health 2024; 24:611. [PMID: 38802844 PMCID: PMC11129485 DOI: 10.1186/s12903-024-04342-2] [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: 02/20/2024] [Accepted: 05/07/2024] [Indexed: 05/29/2024] Open
Abstract
PURPOSE This study aims to elucidate the biological functions of ferroptosis-related genes in periodontitis, along with their correlation to tumor microenvironment (TME) features such as immune infiltration. It aims to provide potential diagnostic markers of ferroptosis for clinical management of periodontitis. METHODS Utilizing the periodontitis-related microarray dataset GSE16134 from the Gene Expression Omnibus (GEO) and a set of 528 ferroptosis-related genes identified in prior studies, this research unveils differentially expressed ferroptosis-related genes in periodontitis. Subsequently, a protein-protein interaction network was constructed. Subtyping of periodontitis was explored, followed by validation through immune cell infiltration and gene set enrichment analyses. Two algorithms, randomForest and SVM(Support Vector Machine), were employed to reveal potential ferroptosis diagnostic markers for periodontitis. The diagnostic efficacy, immune correlation, and potential transcriptional regulatory networks of these markers were further assessed. Finally, potential targeted drugs for differentially expressed ferroptosis markers in periodontitis were predicted. RESULTS A total of 36 ferroptosis-related genes (30 upregulated, 6 downregulated) were identified from 829 differentially expressed genes between 9 periodontitis samples and the control group. Subsequent machine learning algorithm screening highlighted 4 key genes: SLC1A5(Solute Carrier Family 1 Member 5), SLC2A14(Solute Carrier Family 1 Member 14), LURAP1L(Leucine Rich Adaptor Protein 1 Like), and HERPUD1(Homocysteine Inducible ER Protein With Ubiquitin Like Domain 1). Exploration of these 4 key genes, supported by time-correlated ROC analysis, demonstrated reliability, while immune infiltration results indicated a strong correlation between key genes and immune factors. Furthermore, Gene Set Enrichment Analysis (GSEA) was conducted for the four key genes, revealing enrichment in GO/KEGG pathways that have a significant impact on periodontitis. Finally, the study predicted potential transcriptional regulatory networks and targeted drugs associated with these key genes in periodontitis. CONCLUSIONS The ferroptosis-related genes identified in this study, including SLC1A5, SLC2A14, LURAP1L, and HERPUD1, may serve as novel diagnostic and therapeutic targets for periodontitis. They are likely involved in the occurrence and development of periodontitis through mechanisms such as immune infiltration, cellular metabolism, and inflammatory chemotaxis, potentially linking the ferroptosis pathway to the progression of periodontitis. Targeted drugs such as flurofamide, L-733060, memantine, tetrabenazine, and WAY-213613 hold promise for potential therapeutic interventions in periodontitis associated with these ferroptosis-related genes.
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Affiliation(s)
- Jili Chen
- Department of Periodontics, Panyu Branch, Stomatological Hospital, School of Stomatology, Southern Medical University, No.366 Jiangnan Dadao Nan, Haizhu District, Guangzhou, Guangdong, 510220, China
| | - Lijia Ou
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, No. 172 Tongzipo Road, Yuelu District, Changsha, 410006, China
| | - Weizhen Liu
- Department of Periodontics, Panyu Branch, Stomatological Hospital, School of Stomatology, Southern Medical University, No.366 Jiangnan Dadao Nan, Haizhu District, Guangzhou, Guangdong, 510220, China
| | - Feng Gao
- Department of Periodontics, Panyu Branch, Stomatological Hospital, School of Stomatology, Southern Medical University, No.366 Jiangnan Dadao Nan, Haizhu District, Guangzhou, Guangdong, 510220, China.
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15
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Pandey P, Elsori D, Kumar R, Lakhanpal S, Rautela I, Alqahtani TM, Ahmad F, Iqbal D, Khan F. Ferroptosis targeting natural compounds as a promising approach for developing potent liver cancer agents. Front Pharmacol 2024; 15:1399677. [PMID: 38738178 PMCID: PMC11082342 DOI: 10.3389/fphar.2024.1399677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 04/04/2024] [Indexed: 05/14/2024] Open
Abstract
Liver cancer is the second leading cause of cancer-related death worldwide. However, treatment options, including surgical resection, transplantation, and molecular drug therapies, are of limited effectiveness. Recent studies have demonstrated that suppressing ferroptosis might be a pivotal signal for liver cancer initiation, thus providing a new way to combat liver cancer. Ferroptosis is a distinct form of controlled cell death that differs from conventional cell death routes like apoptosis, necrosis, and pyroptosis. It results from intracellular iron overload, which raises iron-dependent reactive oxygen species. This, in turn, leads to the accumulation of lipid peroxides that further result in oxidative damage to cell membranes, disrupt normal functioning, and ultimately speed up the ferroptosis phenomenon. Ferroptosis regulation is intricately linked to cellular physiological processes, encompassing iron metabolism, lipid metabolism, and the equilibrium between oxygen-free radical reactions and lipid peroxidation. This review intends to summarize the natural compounds targeting ferroptosis in liver cancer to offer new therapeutic ideas for liver cancer. Furthermore, it serves as the foundation for identifying and applying chemical medicines and natural chemicals that target ferroptosis to treat liver cancer efficiently.
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Affiliation(s)
- Pratibha Pandey
- Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India
| | - Deena Elsori
- Faculty of Resilience, Rabdan Academy, Abu Dhabi, United Arab Emirates
| | - Rahul Kumar
- Chitkara Centre for Research and Development, Chitkara University, Baddi, Himachal Pradesh, India
| | - Sorabh Lakhanpal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Indra Rautela
- School of Applied and Life Sciences, Uttaranchal University, Dehradun, India
| | - Tariq Mohammed Alqahtani
- Department of Radiology and Medical Imaging, College of Applied Medical Sciences, Majmaah university, Al Majma’ah, Saudi Arabia
| | - Fuzail Ahmad
- Respiratory Care Department, College of Applied Sciences, Almaarefa University, Riyadh, Saudi Arabia
| | - Danish Iqbal
- Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, Buraydah, Saudi Arabia
| | - Fahad Khan
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
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16
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Zhang CH, Yan YJ, Luo Q. The molecular mechanisms and potential drug targets of ferroptosis in myocardial ischemia-reperfusion injury. Life Sci 2024; 340:122439. [PMID: 38278348 DOI: 10.1016/j.lfs.2024.122439] [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: 11/23/2023] [Revised: 01/07/2024] [Accepted: 01/14/2024] [Indexed: 01/28/2024]
Abstract
Myocardial ischemia-reperfusion injury (MIRI), caused by the initial interruption and subsequent restoration of coronary artery blood, results in further damage to cardiac function, affecting the prognosis of patients with acute myocardial infarction. Ferroptosis is an iron-dependent, superoxide-driven, non-apoptotic form of regulated cell death that is involved in the pathogenesis of MIRI. Ferroptosis is characterized by the accumulation of lipid peroxides (LOOH) and redox disequilibrium. Free iron ions can induce lipid oxidative stress as a substrate of the Fenton reaction and lipoxygenase (LOX) and participate in the inactivation of a variety of lipid antioxidants including CoQ10 and GPX4, destroying the redox balance and causing cell death. The metabolism of amino acid, iron, and lipids, including associated pathways, is considered as a specific hallmark of ferroptosis. This review systematically summarizes the latest research progress on the mechanisms of ferroptosis and discusses and analyzes the therapeutic approaches targeting ferroptosis to alleviate MIRI.
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Affiliation(s)
- Chen-Hua Zhang
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Yu-Jie Yan
- School of Stomatology, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Qi Luo
- School of Basic Medical Science, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
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17
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Nie A, Shen C, Zhou Z, Wang J, Sun B, Zhu C. Ferroptosis: Potential opportunities for natural products in cancer therapy. Phytother Res 2024; 38:1173-1190. [PMID: 38116870 DOI: 10.1002/ptr.8088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/24/2023] [Accepted: 11/25/2023] [Indexed: 12/21/2023]
Abstract
Cancer cells often exhibit defects in the execution of cell death, resulting in poor clinical outcomes for patients with many cancer types. Ferroptosis is a newly discovered form of programmed cell death characterized by intracellular iron overload and lipid peroxidation in the cell membrane. Increasing evidence suggests that ferroptosis is closely associated with a wide variety of physiological and pathological processes, particularly in cancer. Notably, various bioactive natural products have been shown to induce the initiation and execution of ferroptosis in cancer cells, thereby exerting anticancer effects. In this review, we summarize the core regulatory mechanisms of ferroptosis and the multifaceted roles of ferroptosis in cancer. Importantly, we focus on natural products that regulate ferroptosis in cancer cells, such as terpenoids, polyphenols, alkaloids, steroids, quinones, and polysaccharides. The clinical efficacy, adverse effects, and drug-drug interactions of these natural products need to be evaluated in further high-quality studies to accelerate their application in cancer treatment.
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Affiliation(s)
- Anzheng Nie
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chaozan Shen
- Department of Clinical Pharmacy, The Second People's Hospital of Huaihua, Huaihua, China
| | - Zheng Zhou
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Juan Wang
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chunsheng Zhu
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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18
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Luo X, Ye Z, Xu C, Chen H, Dai S, Chen W, Bao G. Corosolic acid enhances oxidative stress-induced apoptosis and senescence in pancreatic cancer cells by inhibiting the JAK2/STAT3 pathway. Mol Biol Rep 2024; 51:176. [PMID: 38252208 DOI: 10.1007/s11033-023-09105-w] [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: 09/26/2023] [Accepted: 12/05/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND Pancreatic cancer (PC) is a fatal human malignancy with a poor prognosis. Corosolic acid (CRA) is a triterpenoid, has been reported to have inhibitory effects on tumor growth. However, the role of CRA on PC has not been explored. Here, we aimed to uncover the molecular mechanisms of CRA in PC progression. METHODS Cell viability, lactate dehydrogenase (LDH) release, cell apoptosis and senescence were detected by cell counting kit-8 (CCK-8), LDH, flow cytometry and senescence associated-β-galactosidase (SA-β-gal) assay. Levels of relevant proteins and oxidative stress (OS) markers were evaluated by Western blot and enzyme-linked immunosorbent assay (ELISA). A xenograft tumor model was established to explore the in vivo effects of CRA on PC. RESULTS We found that CRA inhibited PC cell viability and promoted LDH release in a dose-dependent manner, but had no significant effect on human normal pancreatic ductal epithelial cells HPDE6C7. CRA increased OS-induced cell apoptosis and senescence in HAPC and SW1990 cells. And CRA decreased the levels of anti-apoptotic protein Bcl-2, and elevated the expression of pro-apoptotic protein Bax and senescence-associated proteins P21 and P53. Besides, CRA decreased tumor growth in xenograft models. Furthermore, CRA inactivated the Janus kinase-2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in HAPC and SW1990 cells. Functional experiments demonstrated that activation of the JAK2/STAT3 pathway by the JAK2 activator coumermycin A1 (C-A1) or the STAT3 activator colivelin (col) reduced the contribution effect of OS, apoptosis and senescence by CRA. CONCLUSION Taken together, our findings indicated that CRA exerted anti-cancer effects in PC by inhibiting the JAK2/STAT3 pathway.
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Affiliation(s)
- Xu Luo
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Zhengchen Ye
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Chenglei Xu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Huan Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Shupeng Dai
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Weihong Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Guoqing Bao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming, 650032, Yunnan Province, China.
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19
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Xiao N, Xiong S, Zhou Z, Zhong M, Bai H, Li Q, Tang Y, Xie J. Recent progress in biomaterials-driven ferroptosis for cancer therapy. Biomater Sci 2024; 12:288-307. [PMID: 38189655 DOI: 10.1039/d3bm01832f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Ferroptosis, first suggested in 2012, is a type of non-apoptotic programmed cell death caused by the buildup of lipid peroxidation and marked by an overabundance of oxidized poly unsaturated fatty acids. During the last decade, researchers have uncovered the formation of ferroptosis and created multiple drugs aimed at it, but due to poor selectivity and pharmacokinetics, clinical application has been hindered. In recent years, biomedical discoveries and developments in nanotechnology have spurred the investigation of ferroptosis nanomaterials, providing new opportunities for the ferroptosis driven tumours treatment. Additionally, hydrogels have been widely studied in ferroptosis because of their unique 3D structure and excellent controllability. By using these biomaterials, it is possible to achieve controlled release and targeted delivery of drugs, thus increasing the potency of the drugs and minimizing adverse effects. Therefore, summarizing the biomedical nanomaterials, including hydrogels, used in ferroptosis for cancer therapy is a must. This article provides an overview of ferroptosis, detailing its properties and underlying mechanisms. It also categorizes and reviews the use of various nanomaterials in ferroptosis, along with relevant explanations and illustrations. In addition, we discuss the opportunities and challenges facing the application of nanomaterials in ferroptosis. Finally, the development prospects of this field are prospected. This review is intended to provide a foundation for the development and application of biomedical nanomaterials in ferroptosis.
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Affiliation(s)
- Nianting Xiao
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Su Xiong
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Ziwei Zhou
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Min Zhong
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Huayang Bai
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Qiyu Li
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
| | - Yaqin Tang
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
| | - Jing Xie
- Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China
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20
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Wang Y, Hu J, Wu S, Fleishman JS, Li Y, Xu Y, Zou W, Wang J, Feng Y, Chen J, Wang H. Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases. Signal Transduct Target Ther 2023; 8:449. [PMID: 38072908 PMCID: PMC10711040 DOI: 10.1038/s41392-023-01720-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 09/16/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023] Open
Abstract
Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.
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Affiliation(s)
- Yumin Wang
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, PR China
| | - Jing Hu
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300060, PR China
| | - Shuang Wu
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, PR China
| | - Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Yulin Li
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, PR China
| | - Yinshi Xu
- Department of Outpatient, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, PR China
| | - Wailong Zou
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, PR China
| | - Jinhua Wang
- Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
| | - Yukuan Feng
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China.
| | - Jichao Chen
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, PR China.
| | - Hongquan Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China.
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21
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Su R, Yin J, Ruan X, Chen Y, Wan P, Luo Z. Featured interactome of homocysteine-inducible endoplasmic reticulum protein uncovers novel binding partners in response to ER stress. Comput Struct Biotechnol J 2023; 21:4478-4487. [PMID: 37736299 PMCID: PMC10510068 DOI: 10.1016/j.csbj.2023.09.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/23/2023] Open
Abstract
Homocysteine-inducible endoplasmic reticulum protein (HERP) is an endoplasmic reticulum (ER)-resident protein and important for the adaptation of cellular protein homeostasis by ER-associated degradation (ERAD) system. HERP interactors are critical for cellular viability and the reaction to ER stress. To explore the exact mechanisms by which HERP performed the biological functions, we conducted an interaction analysis of HERP protein in HeLa cells by co-immunoprecipitation (Co-IP) and liquid chromatography-mass spectrometer (LC-MS)/MS coupled with label-free quantification (LFQ). Among the interactome results, 123 proteins significantly interacted with HERP, which leads to numerous biological processes including protein import into nucleus, ubiquitin-dependent ERAD pathway, negative regulation of apoptotic process, and protein transport from ER, along with multiple pathways including several diseases, protein processing in ER, fatty acid metabolism, and steroid biosynthesis. Furthermore, we selected several prey proteins from the interactome data and confirmed that HERP interacted with ancient ubiquitous protein 1 (AUP1), Fas-associated factor family member 2 (FAF2), tripartite motif containing 47 (TRIM47), acyl-CoA synthetase long-chain family member 3 (ACSL3), sequestosome 1 (SQSTM1), and poly(rC) binding protein 2 (PCBP2) by Co-IP and confocal microscopy experiments, respectively. Moreover, the expression and location of several interacted proteins were obviously altered in response to ER stress induced by Thapsigargin stimulation and Enterovirus 71 infection. In conclusion, our findings revealed that the vital proteins interacted with HERP to mediate signaling transduction, thus providing novel clues for the mechanisms of HERP associated with ERAD and metabolism in response to ER stress under physiological and pathological conditions.
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Affiliation(s)
- Rui Su
- Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang 453003, China
- Department of Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China
| | - Jialing Yin
- Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
| | - Xiaolan Ruan
- Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
| | - Yanxi Chen
- Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
| | - Pin Wan
- Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430072, China
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Zhen Luo
- Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
- Foshan Institute of Medical Microbiology, Foshan 528315, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
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22
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Yan X, Liu Y, Li C, Mao X, Xu T, Hu Z, Zhang C, Lin N, Lin Y, Zhang Y. Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis. Cancer Cell Int 2023; 23:109. [PMID: 37280673 PMCID: PMC10246043 DOI: 10.1186/s12935-023-02946-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/15/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation. METHODS A diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the "disease-related gene-drug effective target" interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro. RESULTS PZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats. CONCLUSIONS Our data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.
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Affiliation(s)
- Xiangying Yan
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Yudong Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Congchong Li
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Xia Mao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Tengteng Xu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Zhixing Hu
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Chu Zhang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Na Lin
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China
| | - Ya Lin
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China.
| | - Yanqiong Zhang
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China.
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
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23
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Chetverina D, Vorobyeva NE, Gyorffy B, Shtil AA, Erokhin M. Analyses of Genes Critical to Tumor Survival Reveal Potential 'Supertargets': Focus on Transcription. Cancers (Basel) 2023; 15:cancers15113042. [PMID: 37297004 DOI: 10.3390/cancers15113042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
The identification of mechanisms that underlie the biology of individual tumors is aimed at the development of personalized treatment strategies. Herein, we performed a comprehensive search of genes (termed Supertargets) vital for tumors of particular tissue origin. In so doing, we used the DepMap database portal that encompasses a broad panel of cell lines with individual genes knocked out by CRISPR/Cas9 technology. For each of the 27 tumor types, we revealed the top five genes whose deletion was lethal in the particular case, indicating both known and unknown Supertargets. Most importantly, the majority of Supertargets (41%) were represented by DNA-binding transcription factors. RNAseq data analysis demonstrated that a subset of Supertargets was deregulated in clinical tumor samples but not in the respective non-malignant tissues. These results point to transcriptional mechanisms as key regulators of cell survival in specific tumors. Targeted inactivation of these factors emerges as a straightforward approach to optimize therapeutic regimens.
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Affiliation(s)
- Darya Chetverina
- Group of Epigenetics, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russia
| | - Nadezhda E Vorobyeva
- Group of Dynamics of Transcriptional Complexes, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russia
| | - Balazs Gyorffy
- Departments of Bioinformatics and Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- Cancer Biomarker Research Group, Research Centre for Natural Sciences, Institute of Enzymology, H-1117 Budapest, Hungary
| | - Alexander A Shtil
- Blokhin National Medical Research Center of Oncology, 24 Kashirskoye Shosse, Moscow 115522, Russia
| | - Maksim Erokhin
- Group of Chromatin Biology, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov Street, Moscow 119334, Russia
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24
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Tang FF, Liu L, Tian XT, Li N, Peng YX, Qian CM, Jia TT, Liu JJ, Gao WH, Xu YF. Network pharmacological analysis of corosolic acid reveals P4HA2 inhibits hepatocellular carcinoma progression. BMC Complement Med Ther 2023; 23:171. [PMID: 37248456 DOI: 10.1186/s12906-023-04008-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 05/22/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization. METHODS Differentially expressed proteins of the Bel-7404 cell line were identified with tandem mass tag analysis and differentially expressed genes (DEGs) of an HCC TCGA dataset using bioinformatics. Gene functions and pathways were inferred using the DAVID database. Online databases were used to establish P4HA2 expression in HCC (GEPIA2) and its relationship with patient survival (UALCAN and The Human Protein Atlas), the association between P4HA2 expression and immune cell infiltration (TIMER2), and DNA methylation of the P4HA2 gene (MethSurv). Cell proliferation, cell cycle, and cell death were assessed with PI and SYTOX-Green staining, CCK-8, and colony formation assays. Protein expression levels were detected by Western blotting. RESULTS A total of 44 differentially expressed proteins and 4498 DEGs were identified. Four genes whose proteins were also found in the differential protein profile but with opposing expressions were selected as candidate targets. The candidate gene prolyl 4-hydroxylase subunit alpha 2 (P4HA2) was recognized as the only potential target due to its high expression in public datasets, association with poor patient survival, and relation to immune cell infiltration in HCC tissues. Moreover, the DNA methylation status in 4 CpG islands of the P4HA2 gene correlated with a poor prognosis. Furthermore, corosolic acid treatment inhibited the proliferation of HCC cell lines Bel-7404 and HepG2 in a dose-dependent manner, caused G2/M phase cell cycle arrest, and promoted cell death. In addition, the treatment reduced P4HA2 protein levels. CONCLUSION Our results indicate that P4HA2 is a potential target of corosolic acid. Thus, they contribute to understanding molecular changes in HCC after corosolic acid treatment and facilitate finding new treatment regimens.
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Affiliation(s)
- Fei-Feng Tang
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China
| | - Long Liu
- Department of Traditional Chinese Medicine, Tianyou Hospital of Tongji University, Shanghai, 200331, People's Republic of China
| | - Xiao-Ting Tian
- Shanghai Chest Hospital, Shanghai Institute of Thoracic Oncology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, People's Republic of China
| | - Ning Li
- Central Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China
| | - Ying-Xiu Peng
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China
| | - Chun-Mei Qian
- Central Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China
| | - Ting-Ting Jia
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China
| | - Jing-Jin Liu
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China
| | - Wen-Hui Gao
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China
| | - Yan-Feng Xu
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People's Republic of China.
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25
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Li Z, Chen Z, Li S, Qian X, Zhang L, Long G, Xie J, Huang X, Zheng Z, Pan W, Li H, Zhang D. Circ_0020256 induces fibroblast activation to drive cholangiocarcinoma development via recruitment of EIF4A3 protein to stabilize KLF4 mRNA. Cell Death Discov 2023; 9:161. [PMID: 37179359 PMCID: PMC10183031 DOI: 10.1038/s41420-023-01439-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 04/07/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs) are a kind of stromal cells in the cholangiocarcinoma (CCA) microenvironment, playing crucial roles in cancer development. However, the potential mechanisms of the interaction between CCA cells and CAFs remain obscure. This work investigated the role of circ_0020256 in CAFs activation. We proved circ_0020256 was up-regulated in CCA. High circ_0020256 expression facilitated TGF-β1 secretion from CCA cells, which activated CAFs via the phosphorylation of Smad2/3. Mechanistically, circ_0020256 recruited EIF4A3 protein to stabilize KLF4 mRNA and upregulate its expression, then KLF4 bound to TGF-β1 promoter and induced its transcription in CCA cells. KLF4 overexpression abrogated the inhibition of circ_0020256 silencing in TGF-β1/Smad2/3-induced CAFs activation. Furthermore, CCA cell growth, migration, and epithelial-mesenchymal transition were favored by CAFs-secreted IL-6 via autophagy inhibition. We also found circ_0020256 accelerated CCA tumor growth in vivo. In conclusion, circ_0020256 promoted fibroblast activation to facilitate CCA progression via EIF4A3/KLF4 pathway, providing a potential intervention for CCA progression.
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Affiliation(s)
- Zongyan Li
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Zuxiao Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, P.R. China
| | - Shiying Li
- Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong Province, P.R. China
| | - Xiangjun Qian
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Lei Zhang
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Guojie Long
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Jiancong Xie
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Xiaoming Huang
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Zheyu Zheng
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Weidong Pan
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China
| | - Haiyan Li
- Department of Breast Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China.
| | - Dawei Zhang
- Department of Pancreatic Hepatobiliary Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510650, Guangdong Province, P.R. China.
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26
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Zhang R, Kang R, Tang D. Ferroptosis in gastrointestinal cancer: From mechanisms to implications. Cancer Lett 2023; 561:216147. [PMID: 36965540 DOI: 10.1016/j.canlet.2023.216147] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/16/2023] [Accepted: 03/22/2023] [Indexed: 03/27/2023]
Abstract
Ferroptosis is a form of regulated cell death that is initiated by excessive lipid peroxidation that results in plasma membrane damage and the release of damage-associated molecular patterns. In recent years, ferroptosis has gained significant attention in cancer research due to its unique mechanism compared to other forms of regulated cell death, especially caspase-dependent apoptotic cell death. Gastrointestinal (GI) cancer encompasses malignancies that arise in the digestive tract, including the stomach, intestines, pancreas, colon, liver, rectum, anus, and biliary system. These cancers are a global health concern, with high incidence and mortality rates. Despite advances in medical treatments, drug resistance caused by defects in apoptotic pathways remains a persistent challenge in the management of GI cancer. Hence, exploring the role of ferroptosis in GI cancers may lead to more efficacious treatment strategies. In this review, we provide a comprehensive overview of the core mechanism of ferroptosis and discuss its function, regulation, and implications in the context of GI cancers.
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Affiliation(s)
- Ruoxi Zhang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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27
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Xiang X, Gao J, Su D, Shi D. The advancements in targets for ferroptosis in liver diseases. Front Med (Lausanne) 2023; 10:1084479. [PMID: 36999078 PMCID: PMC10043409 DOI: 10.3389/fmed.2023.1084479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 02/27/2023] [Indexed: 03/16/2023] Open
Abstract
Ferroptosis is a type of regulated cell death caused by iron overload and lipid peroxidation, and its core is an imbalance of redox reactions. Recent studies showed that ferroptosis played a dual role in liver diseases, that was, as a therapeutic target and a pathogenic factor. Therefore, herein, we summarized the role of ferroptosis in liver diseases, reviewed the part of available targets, such as drugs, small molecules, and nanomaterials, that acted on ferroptosis in liver diseases, and discussed the current challenges and prospects.
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Affiliation(s)
- Xiaohong Xiang
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Xiaohong Xiang
| | - Jianbo Gao
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danyang Su
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Doudou Shi
- Department of Geriatrics, The Ninth Hospital of Xi'an, Xi'an, Shaanxi, China
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