Resveratrol (Res) is a polyphenol with a variety of biological activities. However, whether Res can prevent myocardial ischemia–reperfusion (I/R) injury is not yet known. This study aimed to investigate the protective effect of Res on myocardial I/R injury and to explore its potential mechanism. H9c2 cells were used for the in vitro experiments and oxygen-glucose deprivation/reoxygenation (OGD/R) model was established. Rats were ligated and perfused by the left anterior descending branch with or without Res (50 mg/kg·bw) for 14 days.The higher level of oxidative stress and Fe²⁺ content was observed in OGD/R-induced H9c2 cells than that of normal cells. OGD/R-induced H9c2 cells showed increased ferroptosis, mainly by reducing the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1), but enhancing the expression of transferrin receptor 1 (TfR1). Both in vivo and in vitro experiments indicated that Res reduced the level of oxidative stress and Fe2 + content. In addition, Res inhibited ferroptosis, decreased TfR1 expression, and increased the expressions of FTH1 and GPX4 in OGD/R-induced H9c2 cells and I/R rats. Moreover, we found that Res inhibited ferroptosis by the regulation of ubiquity specific peptidase 19 (USP19)-Beclin1 autophagy. Res protects against myocardial I/R injury via reducing oxidative stress and attenuating ferroptosis. Res could be a potential agent to the prevention of myocardial I/R injury.

白藜芦醇 (Res) 是一种具有多种生物活性的多酚。然而，Res 是否可以预防心肌缺血再灌注 (I/R) 损伤尚不清楚。本研究旨在探讨Res对心肌I/R损伤的保护作用并探讨其潜在机制。H9c2细胞用于体外实验并建立氧-葡萄糖剥夺/复氧（OGD/R）模型。大鼠左前降支结扎灌注或不加Res（50 mg/kg·bw）14天。氧化应激和Fe ²⁺水平较高在 OGD/R 诱导的 H9c2 细胞中观察到的含量高于正常细胞。OGD/R 诱导的 H9c2 细胞显示出铁死亡增加，主要是通过降低谷胱甘肽过氧化物酶 4 (GPX4) 和铁蛋白重链 1 (FTH1) 的表达，但增强转铁蛋白受体 1 (TfR1) 的表达。体内外实验均表明 Res 降低了氧化应激水平和 Fe2+ 含量。此外，在OGD/R诱导的H9c2细胞和I/R大鼠中，Res抑制铁死亡，降低TfR1表达，并增加FTH1和GPX4的表达。此外，我们发现 Res 通过调节泛素特异性肽酶 19 (USP19)-Beclin1 自噬来抑制铁死亡。Res 通过减少氧化应激和减弱铁死亡来防止心肌 I/R 损伤。