{"title":"铁下垂和脂质过氧化通过长链酰基辅酶a合成酶4/谷胱甘肽过氧化物酶4途径参与丙戊酸诱导的肝毒性。","authors":"Ying Zhang, Tong Li, Yujia Zhang, Tianyu Xu, Limei Zhao","doi":"10.1002/jbt.70484","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Valproic acid (VPA) is a commonly prescribed antiepileptic drug, with hepatotoxicity being one of its most frequent and severe adverse effects. The underlying mechanisms of VPA-induced hepatotoxicity remain elusive. Thus, this study aimed to investigate the involvement of ferroptosis in VPA-induced hepatotoxicity in vivo and in vitro. C57BL/6 J mice and HepG2 cells were treated with VPA to establish VPA-induced hepatotoxic models. The results demonstrated that VPA not only induced hepatic steatosis but also elevated liver biochemical and oxidative stress indicators, suggesting that VPA-induced hepatotoxicity affects hepatic iron metabolism. Moreover, VPA treatment altered the expression of ferroptosis-related proteins and lipid peroxides, indicating that ferroptosis contributed to VPA-induced hepatotoxicity. To investigate the role of ACSL4, a pivotal enzyme in lipid peroxidation during ferroptosis, in VPA-induced hepatotoxicity, a study was conducted utilizing rosiglitazone (RSG), a specific inhibitor of ACSL4, to interfere with the overexpression of ACSL4 in a model mouse system. Furthermore, an in vitro approach was employed, where ACSL4 siRNA was utilized to knock down ACSL4 expression in a cellular model of VPA-induced hepatotoxicity. This dual-pronged strategy aimed at elucidating the mechanistic contributions of ACSL4 in mediating the deleterious effects of VPA on the liver. In summary, ferroptosis emerges as a novel mechanism underlying VPA-induced hepatotoxicity, and ACSL4 may serve as a crucial target in the process of VPA-induced liver injury. This study has the potential to lay the groundwork for the development of novel therapeutic strategies for treating VPA-induced liver damage.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 10","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ferroptosis and Lipid Peroxidation Participate in Valproic Acid-Induced Hepatotoxicity via the Long-chain Acyl-CoA Synthetase 4/Glutathione Peroxidase 4 Pathway\",\"authors\":\"Ying Zhang, Tong Li, Yujia Zhang, Tianyu Xu, Limei Zhao\",\"doi\":\"10.1002/jbt.70484\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>Valproic acid (VPA) is a commonly prescribed antiepileptic drug, with hepatotoxicity being one of its most frequent and severe adverse effects. The underlying mechanisms of VPA-induced hepatotoxicity remain elusive. Thus, this study aimed to investigate the involvement of ferroptosis in VPA-induced hepatotoxicity in vivo and in vitro. C57BL/6 J mice and HepG2 cells were treated with VPA to establish VPA-induced hepatotoxic models. The results demonstrated that VPA not only induced hepatic steatosis but also elevated liver biochemical and oxidative stress indicators, suggesting that VPA-induced hepatotoxicity affects hepatic iron metabolism. Moreover, VPA treatment altered the expression of ferroptosis-related proteins and lipid peroxides, indicating that ferroptosis contributed to VPA-induced hepatotoxicity. To investigate the role of ACSL4, a pivotal enzyme in lipid peroxidation during ferroptosis, in VPA-induced hepatotoxicity, a study was conducted utilizing rosiglitazone (RSG), a specific inhibitor of ACSL4, to interfere with the overexpression of ACSL4 in a model mouse system. Furthermore, an in vitro approach was employed, where ACSL4 siRNA was utilized to knock down ACSL4 expression in a cellular model of VPA-induced hepatotoxicity. This dual-pronged strategy aimed at elucidating the mechanistic contributions of ACSL4 in mediating the deleterious effects of VPA on the liver. In summary, ferroptosis emerges as a novel mechanism underlying VPA-induced hepatotoxicity, and ACSL4 may serve as a crucial target in the process of VPA-induced liver injury. This study has the potential to lay the groundwork for the development of novel therapeutic strategies for treating VPA-induced liver damage.</p></div>\",\"PeriodicalId\":15151,\"journal\":{\"name\":\"Journal of Biochemical and Molecular Toxicology\",\"volume\":\"39 10\",\"pages\":\"\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2025-09-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Biochemical and Molecular Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70484\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biochemical and Molecular Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70484","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Ferroptosis and Lipid Peroxidation Participate in Valproic Acid-Induced Hepatotoxicity via the Long-chain Acyl-CoA Synthetase 4/Glutathione Peroxidase 4 Pathway
Valproic acid (VPA) is a commonly prescribed antiepileptic drug, with hepatotoxicity being one of its most frequent and severe adverse effects. The underlying mechanisms of VPA-induced hepatotoxicity remain elusive. Thus, this study aimed to investigate the involvement of ferroptosis in VPA-induced hepatotoxicity in vivo and in vitro. C57BL/6 J mice and HepG2 cells were treated with VPA to establish VPA-induced hepatotoxic models. The results demonstrated that VPA not only induced hepatic steatosis but also elevated liver biochemical and oxidative stress indicators, suggesting that VPA-induced hepatotoxicity affects hepatic iron metabolism. Moreover, VPA treatment altered the expression of ferroptosis-related proteins and lipid peroxides, indicating that ferroptosis contributed to VPA-induced hepatotoxicity. To investigate the role of ACSL4, a pivotal enzyme in lipid peroxidation during ferroptosis, in VPA-induced hepatotoxicity, a study was conducted utilizing rosiglitazone (RSG), a specific inhibitor of ACSL4, to interfere with the overexpression of ACSL4 in a model mouse system. Furthermore, an in vitro approach was employed, where ACSL4 siRNA was utilized to knock down ACSL4 expression in a cellular model of VPA-induced hepatotoxicity. This dual-pronged strategy aimed at elucidating the mechanistic contributions of ACSL4 in mediating the deleterious effects of VPA on the liver. In summary, ferroptosis emerges as a novel mechanism underlying VPA-induced hepatotoxicity, and ACSL4 may serve as a crucial target in the process of VPA-induced liver injury. This study has the potential to lay the groundwork for the development of novel therapeutic strategies for treating VPA-induced liver damage.
期刊介绍:
The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.