SENP2-mediated deSUMOylation of NCOA4 protects against ferritinophagy-dependent ferroptosis in myocardial ischemia-reperfusion injury

Myocardial ischemia-reperfusion (MI/R) injury is a leading cause of morbidity and mortality around the world, characterized by injury to cardiomyocytes that leads to various forms of cell death, including necrosis, apoptosis, autophagy, and ferroptosis. Preventing cell death is crucial for preserving cardiac function after ischemia-reperfusion injury. Ferroptosis, a novel type of cell death, has recently been identified as a key driver of cardiomyocyte death following MI/R. However, the complex regulatory mechanisms involved in ferroptosis remain unclear. Here, we found that SENP2 expression decreased following myocardial ischemia reperfusion injury. Deletion of <i>SENP2</i> increased cardiomyocyte ferroptosis and hindered cardiac function recovery after MI/R injury, whereas overexpression of SENP2 significantly reduced cardiomyocyte ferroptosis and mitigated MI/R injury. Mechanistically, SENP2 removed the SUMOylation of NCOA4 modified by SUMO1 at K81, K343, and K600 sites. The level of NCOA4 SUMOylation regulated ferritinophagy-dependent ferroptosis through affecting NCOA4 protein stability. SENP2-mediated NCOA4 deSUMOylation alleviated the interaction between NCOA4 and OTUB1, which directly deubiquitinated NCOA4 and maintained its protein stability. Furthermore, administration of SENP2 in the animal MI/R model reduced ferroptosis events, protected the injured myocardium and promoted cardiac function recovery. Collectively, our results demonstrate that SENP2 catalyzes deSUMOylation of NCOA4, alleviates ferritinophagy-mediated ferroptosis in an OTUB1-dependent manner, thereby facilitating cardiac function recovery following MI/R. These findings suggest a potential therapeutic strategy for MI/R treatment. <b>Abbreviations</b>: I/R: ischemia-reperfusion; MI/R: myocardial ischemia-reperfusion; NCOA4: nuclear receptor coactivator 4; OTUB1: OTU domain, ubiquitin aldehyde binding 1; SENP2: SUMO/sentrin specific peptidase 2