Ferroptosis is a new regulated cells death manner defined as results of iron-dependent accumulation of lipid peroxidation. However, the specific mechanisms of regulating ferroptosis remain unclear. In our present study, we demonstrated that Caveolin-1 (Cav-1) played a central role in protecting hepatocytes against ferroptosis in autoimmunity-mediated hepatitis (AIH). The down-regulated Cav-1 in liver tissues, accompanied by ferroptotic events and RNS production, were contributed to the outcome of ConA-induced hepatic damage, which were rescued by ferrostatin-1 (an inhibitor of ferroptosis) in vivo and in vitro. Additionally, Cav-1 deficiency aggravated ConA-induced hepatocellular death and ferroptosis associated with excessive nitrogen stress response. Short hairpin RNA of Cav-1 in hepatocytes promoted ferroptosis and nitrative stress in response to erastin in vitro, which was ameliorated by Cav-1 over-expression. Meanwhile, administration of the iNOS inhibitor (1400W) or ONOO- scavenger (Fe-TMPyP), diminished reactive nitrogen species (RNS), remarkably reduced hepatocytes ferroptosis and attenuated ConA-induced liver damage. Furthermore, immune inhibition by gadolinium chloride (GdCl3), a well-known Kupffer cell depletor, elevated hepatic Cav-1 but inhibited ferroptosis and nitrative stress under ConA exposure. In conclusion, these data revealed a novel molecular mechanism of ferroptosis with the Cav-1 regulation was essential for pathogenesis of ConA-induced hepatitis. Downstream of Cav-1, RNS-mediated ferroptosis was a pivotal step that drives the execution of acute immune-mediated hepatic damage.

中文翻译：

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Caveolin-1通过减轻氮胁迫在急性免疫介导的肝损伤的执行过程中指示肥大症。

Ferroptosis是一种新的调控细胞死亡的方式，定义为脂质过氧化铁依赖性累积的结果。但是，调节铁锈病的具体机制仍不清楚。在我们目前的研究中，我们证明了在自身免疫介导的肝炎（AIH）中，Caveolin-1（Cav-1）在保护肝细胞免受ferroptosis方面起着核心作用。肝组织中Cav-1的下调，伴随着促肥性事件和RNS的产生，是ConA诱导的肝损伤的结果，其在体内和体外都通过ferrostatin-1（促肥大症的抑制剂）得以挽救。此外，Cav-1缺乏症加剧了ConA诱导的肝细胞死亡和与过度氮胁迫反应相关的肥大症。肝细胞中Cav-1的短发夹RNA响应体外蛋白刺激促进肥大病和硝化应激，而Cav-1的过表达改善了这种现象。同时，施用iNOS抑制剂（1400W）或ONOO-清除剂（Fe-TMPyP），减少了活性氮物质（RNS），显着减少了肝细胞肥大症并减轻了ConA诱导的肝损伤。此外，众所周知的Kupffer细胞耗竭剂氯化g（GdCl3）对免疫的抑制作用使肝Cav-1升高，但在ConA暴露下抑制了肥大病和硝化应激。总之，这些数据揭示了具有Cav-1调节作用的新型肥大症分子机制对于ConA诱发的肝炎的发病机理至关重要。Cav-1的下游，