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Thus, this study aimed to investigate the involvement of ferroptosis in VPA\u2010induced hepatotoxicity in vivo and in vitro. C57BL\/6\u2009J mice and HepG2 cells were treated with VPA to establish VPA\u2010induced hepatotoxic models. The results demonstrated that VPA not only induced hepatic steatosis but also elevated liver biochemical and oxidative stress indicators, suggesting that VPA\u2010induced hepatotoxicity affects hepatic iron metabolism. Moreover, VPA treatment altered the expression of ferroptosis\u2010related proteins and lipid peroxides, indicating that ferroptosis contributed to VPA\u2010induced hepatotoxicity. To investigate the role of ACSL4, a pivotal enzyme in lipid peroxidation during ferroptosis, in VPA\u2010induced 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\u2010induced hepatotoxicity. This dual\u2010pronged 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\u2010induced hepatotoxicity, and ACSL4 may serve as a crucial target in the process of VPA\u2010induced liver injury. This study has the potential to lay the groundwork for the development of novel therapeutic strategies for treating VPA\u2010induced liver damage.<\/jats:p>","DOI":"10.1002\/jbt.70484","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T14:35:15Z","timestamp":1758724515000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ferroptosis and Lipid Peroxidation Participate in Valproic Acid\u2010Induced Hepatotoxicity via the Long\u2010chain Acyl\u2010CoA Synthetase 4\/Glutathione Peroxidase 4 Pathway"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9249-974X","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy Shengjing Hospital of China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shengjing Hospital of China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shengjing Hospital of China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shengjing Hospital of China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shengjing Hospital of China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"issue":"10","key":"e_1_2_9_2_1","article-title":"Valproic Acid, Valproate and Divalproex in the Maintenance Treatment of Bipolar Disorder","author":"Cipriani A.","year":"2013","journal-title":"Cochrane Common Mental Disorders Group"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.2165\/00148581-200608020-00004"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-200216100-00003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30107-8"},{"key":"e_1_2_9_6_1","first-page":"1573","article-title":"Mechanisms of Amiodarone and Valproic Acid Induced Liver Steatosis in Mouse In Vivo Act as a Template for Other Hepatotoxicity Models","volume":"88","author":"Vitins A. 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