ArticleBasic research in cardiology2026
P38α deficiency alleviates myocardial ischemia/reperfusion injury by stabilizing c‑Myc to inhibit ferroptosis.
Article in Basic research in cardiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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