Cardiomyocyte-derived GPX4 significantly reduces myocardial damage and mitochondrial dysfunction in myocardial ischemia/reperfusion injury by stabilizing BNIP3 to promote mitophagy.
Does cardiomyocyte-derived GPX4 overexpression reduce myocardial damage and improve cardiac function in models of myocardial ischemia/reperfusion injury?
Cardiomyocyte-derived GPX4 protects against myocardial ischemia/reperfusion injury and adverse ventricular remodeling by stabilizing BNIP3 and promoting mitophagy.
GPX4 is a crucial regulator of ferroptosis, yet its role in mitochondrial dysfunction during myocardial ischemia/reperfusion injury (MI/RI) is unclear. This study aims to clarify the effect and molecular mechanisms of GPX4 in MI/RI. We analyzed the spatiotemporal dynamics of GPX4 during MI/RI and observed high expression levels in border and normal areas but a significant reduction in the ischemic region utilizing spatial transcriptomics, spatial proteomics, and single-cell sequencing. Cardiomyocyte-derived GPX4 notably reduces myocardial damage and mitochondrial dysfunction in MI/RI while also alleviating long-term ventricular remodeling. Mechanistically, our findings reveal that GPX4, through its critical U46 active site, enhances the interaction between BNIP3 and USP20, decreasing ubiquitination at K131 of BNIP3. This process stabilizes BNIP3, promotes mitophagy, improves mitochondrial function, and ultimately preserves cardiac function. Our research defines the role of the GPX4/BNIP3/USP20 complex in MI/RI and uncovers a mechanism linking GPX4 to ferroptosis-related mitochondrial damage, providing valuable insights for advancing ferroptosis studies.
Zhong et al. (2026) studied Myocardial ischemia/reperfusion injury. GPX4 overexpression vs. Empty vector was evaluated on Myocardial infarct size and cardiac function. Cardiomyocyte-derived GPX4 significantly reduces myocardial damage and mitochondrial dysfunction in myocardial ischemia/reperfusion injury by stabilizing BNIP3 to promote mitophagy.