OXCT1-mediated succinylation of SLC25A11 protects against myocardial ischemia-reperfusion injury by inhibiting ferroptosis

Abstract Protein succinylation is increasingly recognized for its pivotal role in cardiovascular pathophysiology, yet the specific function of succinyl-CoA:3-ketoacid CoA transferase 1 (OXCT1) in myocardial ischemia/reperfusion (I/R) injury remains to be fully elucidated. In this study, we identify OXCT1 as a critical anti-ferroptotic regulator that protects the myocardium against I/R-induced damage. Using cardiomyocyte-specific OXCT1 ablation and overexpression mouse models, we observed that while OXCT1 expression is significantly upregulated following I/R injury, its deficiency exacerbates cardiac dysfunction and ferroptosis, whereas its replenishment confers robust cardioprotection. Mechanistically, through RNA-seq and co-immunoprecipitation followed by mass spectrometry (IP/MS), we identified the mitochondrial glutathione (GSH) transporter SLC25A11 as a direct interacting partner and succinylation substrate of OXCT1. We demonstrate that OXCT1 mediates the succinylation of SLC25A11 at the K256 residue, which competitively inhibits its ubiquitination-mediated degradation. The resulting stabilization of SLC25A11 is essential for maintaining mitochondrial GSH homeostasis, thereby suppressing cardiomyocyte ferroptosis and mitigating I/R injury. Our findings reveal a novel molecular switch involving OXCT1-mediated succinylation and suggest that targeting the OXCT1-SLC25A11 axis represents a promising therapeutic strategy for minimizing cardiac dysfunction following I/R injury.