A critical pathogenic factor in the development of lethal liver failure is cell death induced by the accumulation of lipid reactive oxygen species. In this study, we discovered and illuminated a new mechanism that led to alcoholic liver disease via ferroptosis, an iron-dependent regulated cell death. Study in vitro showed that both necroptosis inhibitor and ferroptosis inhibitors performed significantly protective effect on alcohol-induced cell death, while apoptosis inhibitor and autophagy inhibitor had no such effect. Our data also indicated that alcohol caused the accumulation of lipid peroxides and the mRNA expression of prostaglandin-endoperoxide synthase 2, reduced the protein expression of the specific light-chain subunit of the cystine/glutamate antiporter and glutathione peroxidase 4. Importantly, ferrostatin-1 significantly ameliorated liver injury that was induced by overdosed alcohol both in vitro and in vivo. These findings highlight that targeting ferroptosis serves as a hepatoprotective strategy for alcoholic liver disease treatment.

致死性肝衰竭发展中的关键致病因素是脂质反应性氧的积累引起的细胞死亡。在这项研究中，我们发现并阐明了一种新的机制，该机制可通过肥大症（一种铁依赖性调节的细胞死亡）导致酒精性肝病。研究体外结果表明，坏死病抑制剂和铁生病抑制剂均对酒精诱导的细胞死亡具有明显的保护作用，而凋亡抑制剂和自噬抑制剂则无此作用。我们的数据还表明，酒精引起脂质过氧化物的积累，前列腺素-过氧化物合酶2的mRNA表达降低了胱氨酸/谷氨酸逆转运蛋白和谷胱甘肽过氧化物酶4特定轻链亚基的蛋白表达。重要的是，ferrostatin-1显著改善肝损伤的是诱导二者过量醇在体外和体内。这些发现突出表明，针对肥大症可以作为酒精性肝病治疗的保肝策略。