Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron overload and excessive lipid peroxides, is reportedly involved in I/R injury. However, its significance and mechanistic basis remain unclear. Here, we show that glutathione peroxidase 4 (GPx4), a key endogenous suppressor of ferroptosis, determines the susceptibility to myocardial I/R injury. Importantly, ferroptosis is a major mode of cell death in I/R injury, distinct from mitochondrial permeability transition (MPT)–driven necrosis. This suggests that the use of therapeutics targeting both modes is an effective strategy to further reduce the infarct size and thereby ameliorate cardiac remodeling after I/R injury. Furthermore, we demonstrate that heme oxygenase 1 up-regulation in response to hypoxia and hypoxia/reoxygenation degrades heme and thereby induces iron overload and ferroptosis in the endoplasmic reticulum (ER) of cardiomyocytes. Collectively, ferroptosis triggered by GPx4 reduction and iron overload in the ER is distinct from MPT-driven necrosis in both in vivo phenotype and in vitro mechanism for I/R injury. The use of therapeutics targeting ferroptosis in conjunction with cyclosporine A can be a promising strategy for I/R injury.

缺血再灌注（I/R）损伤是改善急性心肌梗死后临床结果的有前景的治疗靶点。据报道，由铁过载和过量脂质过氧化物引发的铁死亡与 I/R 损伤有关。然而，其意义和机制基础仍不清楚。在这里，我们发现谷胱甘肽过氧化物酶 4 (GPx4) 是铁死亡的关键内源性抑制因子，它决定了对心肌 I/R 损伤的易感性。重要的是，铁死亡是 I/R 损伤中细胞死亡的主要模式，与线粒体通透性转变 (MPT) 驱动的坏死不同。这表明使用针对这两种模式的治疗方法是进一步减少梗塞面积并从而改善 I/R 损伤后心脏重塑的有效策略。此外，我们证明，缺氧和缺氧/复氧反应中血红素加氧酶 1 上调会降解血红素，从而诱导心肌细胞内质网 (ER) 中的铁过载和铁死亡。总的来说，由 GPx4 减少和 ER 中铁超载引发的铁死亡在体内表型和体外 I/R 损伤机制上都不同于 MPT 驱动的坏死。使用针对铁死亡的疗法与环孢菌素 A 联合使用可能是治疗 I/R 损伤的一种有前途的策略。