Exposure to arsenic is a risk factor for nonalcoholic steatohepatitis (NASH). Ferroptosis is a form of regulated cell death defined by the accumulation of lipid peroxidation. In the current study, we observed the occurrence of ferroptosis in arsenic-induced NASH by assessing ferroptosis related hallmarks. In vitro, we found that ferrostatin-1 effectively attenuated the executing of ferroptosis and NASH. Simultaneously, the expression of ACSL4 (acyl-CoA synthetase long-chain family member 4) was upregulated in rat's liver and L-02 cells exposed to arsenic. While, suppression of ACSL4 with rosiglitazone or ACSL4 siRNA remarkably alleviated arsenic-induced NASH and ferroptosis through diminishing 5-hydroxyeicosatetraenoic acid (5-HETE) content. Additionally, Mitofusin 2 (Mfn2), a physical tether between endoplasmic reticulum and mitochondria, has rarely been explored in the ferroptosis. Using Mfn2 siRNA or inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, we found NASH and ferroptosis were obviously mitigated through reducing 5-HETE content. Importantly, Co-IP assay indicated that Mfn2 could interact with IRE1α and promoted the production of 5-HETE, ultimately led to ferroptosis and NASH. Collectively, our data showed that ferroptosis is involved in arsenic-induced NASH. These data provide insightful viewpoints into the mechanism of arsenic-induced NASH.

接触砷是非酒精性脂肪性肝炎 (NASH) 的危险因素。铁死亡是一种受调节的细胞死亡形式，由脂质过氧化的积累定义。在目前的研究中，我们通过评估铁死亡相关标志来观察砷诱导的 NASH 中铁死亡的发生。体外，我们发现 ferrostatin-1 有效地减弱了铁死亡和 NASH 的发生。同时，在暴露于砷的大鼠肝脏和 L-02 细胞中，ACSL4（酰基辅酶A 合成酶长链家族成员 4）的表达上调。而用罗格列酮或 ACSL4 siRNA 抑制 ACSL4 通过减少 5-羟基二十碳四烯酸 (5-HETE) 含量显着减轻了砷诱导的 NASH 和铁死亡。此外，Mitofusin 2 (Mfn2) 是内质网和线粒体之间的物理系绳，在铁死亡中很少被探索。使用 Mfn2 siRNA 或肌醇需要酶 1 α (IRE1α) 抑制剂，我们发现 NASH 和铁死亡通过减少 5-HETE 含量明显减轻。重要的是，Co-IP 分析表明 Mfn2 可以与 IRE1α 相互作用并促进 5-HETE 的产生，最终导致铁死亡和 NASH。总的来说，我们的数据表明，铁死亡与砷诱导的 NASH 相关。这些数据为砷诱导的 NASH 机制提供了深刻的观点。