Hypoxia Aggravates Myocardial Ischemia/Reperfusion Injury Through the Promotion of Ferroptosis via ACSL4 Lactylation

Myocardial ischemia/reperfusion injury (MIRI) worsens ischemic damage, with Ferroptosis as a key mediator of this iron-dependent cell death. Lactylation, a novel epigenetic modification, remains poorly understood in MIRI-associated Ferroptosis. This study aimed to elucidate the mechanistic link between lactylation and Ferroptosis in MIRI. Experimental results demonstrated that hypoxia/reoxygenation (H/R) induction combined with lactate (LA) treatment significantly enhanced the protein expression levels, lactylation status, and protein stability of acyl-CoA synthetase long-chain family member 4 (ACSL4). Site-specific analysis identified lysine 83 (K83) as the critical lactylation modification site on ACSL4. Functional studies revealed that LDHA knockdown-mediated suppression of lactate levels attenuated Ferroptosis in H/R-treated cells, an effect that was reversed by ACSL4 overexpression. In vivo validation confirmed that LDHA depletion ameliorated ferroptosis-related damage and mitigated MIRI-induced cardiac dysfunction. Collectively, these findings establish that lactylation-regulated ACSL4 Ferroptosis exacerbates MIRI pathogenesis, suggesting that targeting the lactylation-ACSL4 axis represents a promising therapeutic strategy for MIRI.

ACSL4; Ferroptosis; Hypoxia/reoxygenation; Lactylation; Myocardial ischemia/reperfusion injury.