Uncoupling Protein 2 Alleviates Myocardial Ischemia/Reperfusion Injury by Inhibiting Cardiomyocyte Ferroptosis

<b><i>Introduction:</i></b> Following our recent finding that <i>Ucp2</i> knockout promotes ferroptosis, we aimed to examine whether UCP2 alleviates myocardial ischemia/reperfusion injury (MI/RI) by inhibiting ferroptosis. <b><i>Methods:</i></b> The left anterior descending coronary arteries of wild-type and <i>Ucp2</i>^{<i>−/−</i>} C57BL/6 mice were ligated for 30 min and reperfused for 2 h to establish an MI/RI model. The effects of UCP2 on ferroptosis and MI/RI were determined by echocardiography, 2,3,5-triphenylttrazolium chloride staining, hematoxylin-eosin staining, Masson’s trichrome staining, Sirius red staining, and analysis of myocardial injury markers and ferroptosis indicators. Ferrostatin-1 (Fer-1) and erastin (Era) were used to investigate whether UCP2 alleviated MI/RI by inhibiting ferroptosis and the molecular mechanism. <b><i>Results:</i></b> UCP2 was upregulated in the MI/RI model in WT mice. Deletion of <i>Ucp2</i> exacerbated ferroptosis, altered the expression levels of multiple ferroptosis-related genes, and significantly exacerbated MI/RI. Knockout of <i>Ucp2</i> promoted ferroptosis induced by Era and inhibited the antiferroptotic effects of Fer-1. Knockout of <i>Ucp2</i> activated the p53/TfR1 pathway to exacerbate ferroptosis. <b><i>Conclusion:</i></b> Our results showed that UCP2 inhibited ferroptosis in MI/RI, which might be related to regulation of the p53/TfR1 pathway.