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

作者：Siyuan Xue, Jiaxin Zeng, Jingzhe Hao, Wanzhi Cai, Yuxuan Ding, Yuelin Chao, Zong Miao, Zong Miao, Guanhua Xu, Guanhua Xu, Lei Xu, Lei Xu, Zeyu Jiang · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2504792 · 被引用次数：19 · 研究领域：Ferroptosis and cancer prognosis、Circular RNAs in diseases、RNA modifications and cancer

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 SENP2 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...