Ferroptosis and Lipid Peroxidation Participate in Valproic Acid-Induced Hepatotoxicity via the Long-chain Acyl-CoA Synthetase 4/Glutathione Peroxidase 4 Pathway

IF 2.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ying Zhang, Tong Li, Yujia Zhang, Tianyu Xu, Limei Zhao
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Abstract

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.

Abstract Image

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。
丙戊酸(VPA)是一种常用的抗癫痫药物,肝毒性是其最常见和最严重的副作用之一。vpa诱导肝毒性的潜在机制尚不清楚。因此,本研究旨在探讨铁下垂在vpa诱导的体内和体外肝毒性中的作用。采用VPA处理C57BL/6 J小鼠和HepG2细胞,建立VPA诱导的肝毒性模型。结果表明,VPA不仅引起肝脏脂肪变性,还引起肝脏生化和氧化应激指标升高,提示VPA引起的肝毒性影响肝铁代谢。此外,VPA处理改变了铁下垂相关蛋白和脂质过氧化物的表达,表明铁下垂有助于VPA诱导的肝毒性。为了研究ACSL4在vpa诱导的肝毒性中的作用,我们利用ACSL4特异性抑制剂罗格列酮(RSG)在模型小鼠系统中干扰ACSL4的过表达。此外,采用体外方法,利用ACSL4 siRNA在vpa诱导的肝毒性细胞模型中敲低ACSL4的表达。这种双管齐下的策略旨在阐明ACSL4在介导VPA对肝脏的有害作用中的机制贡献。综上所述,铁下垂是vpa诱导肝毒性的一种新机制,ACSL4可能是vpa诱导肝损伤过程中的一个重要靶点。这项研究有可能为开发新的治疗vpa引起的肝损伤的治疗策略奠定基础。
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来源期刊
CiteScore
5.80
自引率
2.80%
发文量
277
审稿时长
6-12 weeks
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.
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