Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to various forms of cell death. It is believed that irreversible myocardial damage resulted from I/R occurs due to oxidative stress evoked during the reperfusion phase. Here we demonstrate that ischemia triggers a specific redox reaction of polyunsaturated fatty acids (PUFA)-phospholipids in myocardial cells, which acts as a priming signaling that initiates the outbreak of robust oxidative damage in the reperfusion phase. Using animal and in vitro models, the crucial lipid species in I/R injury were identified to be oxidized PUFAs enriched phosphatidylethanolamines. Using multi-omics, arachidonic acid 15-lipoxygenase-1 (ALOX15) was identified as the primary mediator of ischemia-provoked phospholipid peroxidation, which was further confirmed using chemogenetic approaches. Collectively, our results reveal that ALOX15 induction in the ischemia phase acts as a “burning point” to ignite phospholipid oxidization into ferroptotic signals. This finding characterizes a novel molecular mechanism for myocardial ischemia injury and offers a potential therapeutic target for early intervention of I/R injury.

心肌缺血/再灌注 (I/R) 损伤是一种典型的心血管疾病，其特征是心肌细胞损伤导致各种形式的细胞死亡。据信，I/R 导致的不可逆心肌损伤是由于在再灌注阶段引起的氧化应激而发生的。在这里，我们证明缺血会触发心肌细胞中多不饱和脂肪酸 (PUFA)-磷脂的特异性氧化还原反应，它作为启动信号在再灌注阶段引发强烈的氧化损伤。使用动物和体外模型，I/R 损伤中的关键脂质种类被鉴定为富含氧化 PUFA 的磷脂酰乙醇胺。使用多组学，花生四烯酸 15-脂氧合酶-1 (ALOX15) 被确定为缺血引起的磷脂过氧化的主要介质，使用化学遗传学方法进一步证实了这一点。总的来说，我们的结果表明，ALOX15 在缺血期的诱导作用是一个“燃点”，可以将磷脂氧化转化为铁死亡信号。这一发现表征了心肌缺血损伤的新分子机制，并为 I/R 损伤的早期干预提供了潜在的治疗靶点。