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.