P38α deficiency alleviates myocardial ischemia/reperfusion injury by stabilizing c‑Myc to inhibit ferroptosis

Myocardial ischemia/reperfusion (I/R) injury constitutes a major clinical challenge in ischemic heart disease, and ferroptosis has been recognized as a core driver of cardiomyocyte death during reperfusion. However, the upstream regulatory network governing myocardial ferroptosis remains incompletely defined. The mitogen-activated protein kinase 14 (p38α, MAPK14) is a stress-activated kinase critically involved in cardiac pathophysiology, yet its role in I/R-induced ferroptosis remains unclear. Here, we report that p38α deficiency attenuates ferroptosis and protects against myocardial I/R injury by stabilizing c-Myc. Phosphorylated p38α (p-p38α) was significantly elevated in mouse hearts after I/R and in cardiomyocytes following oxygen-glucose deprivation/reperfusion (OGD/R). Cardiomyocyte-specific p38α knockout markedly reduced ferroptosis, myocardial infarct size, and cardiac dysfunction. Mechanistically, p-p38α interacts with c-Myc under I/R stress via key residues Arg291, Arg300, and Lys304 of c-Myc and promotes the recruitment of the E3 ubiquitin ligase STUB1, thereby enhancing ubiquitination at Lys51 (K51) of c-Myc and its proteasomal degradation. Loss of p38α stabilizes c-Myc protein and reverses this process. Furthermore, c-Myc acts as a transcriptional repressor of NCOA4, a core mediator of ferroptosis. I/R-induced downregulation of c-Myc relieves NCOA4 suppression, triggering iron overload, lipid peroxidation, and ferroptosis. Overexpression of c-Myc or inhibition of STUB1 or NCOA4 abolished the pro-ferroptotic effect of I/R. Pretreatment with the p38α inhibitor VX-745 recapitulated the cardioprotective effects by restoring the p38α/c-Myc/NCOA4 axis in vivo. Collectively, our findings identify the p38α/c-Myc/NCOA4 signaling axis as a regulatory cascade governing myocardial I/R-induced ferroptosis. These findings nominate the p38α/c-Myc/NCOA4 axis as a potential therapeutic target in myocardial I/R injury.