Phospholipid peroxidation of polyunsaturated fatty acids at the bis-allylic position drives ferroptosis. Here we identify a novel role for phospholipid peroxidation in the inhibition of autophagy. Using in vitro and in vivo models, we report that phospholipid peroxidation induced by glutathione peroxidase-4 inhibition and arachidonate 15-lipoxygenase overexpression leads to overload of peroxidized phospholipids and culminate in inhibition of autophagy. Functional and lipidomics analysis further demonstrated that inhibition of autophagy was associated with an increase of peroxidized phosphatidylethanolamine (PE) conjugated LC3. We further demonstrate that autophagy inhibition occurred due to preferential cleavage of peroxidized LC3-PE by ATG4B to yield delipidated LC3. Mouse models of phospholipid peroxidation and autophagy additionally supported a role for peroxidized PE in autophagy inhibition. Our results agree with the recognized role of endoplasmic reticulum as the primary source for autophagosomal membranes. In summary, our studies demonstrated that phospholipid peroxidation inhibited autophagy via stimulating the ATG4B-mediated delipidation of peroxidized LC3-PE.

双烯丙基位置多不饱和脂肪酸的磷脂过氧化会导致铁死亡。在这里，我们确定了磷脂过氧化在抑制自噬中的新作用。使用体外和体内模型，我们报告谷胱甘肽过氧化物酶 4 抑制和花生四烯酸 15-脂氧合酶过度表达诱导的磷脂过氧化导致过氧化磷脂超载，并最终抑制自噬。功能和脂质组学分析进一步表明，自噬的抑制与过氧化磷脂酰乙醇胺 (PE) 缀合的 LC3 的增加有关。我们进一步证明，自噬抑制的发生是由于 ATG4B 优先裂解过氧化的 LC3-PE，产生脱脂的 LC3。磷脂过氧化和自噬的小鼠模型还支持过氧化 PE 在自噬抑制中的作用。我们的结果与内质网作为自噬体膜的主要来源的公认作用一致。总之，我们的研究表明，磷脂过氧化通过刺激 ATG4B 介导的过氧化 LC3-PE 脱脂来抑制自噬。