Endogenous H₂S promotes HSPA8 sulfhydration to downregulate HIF1α and prevent ferroptosis in septic myocardial injury

Sepsis-induced myocardial injury (SIMI) contributes significantly to morbidity and mortality in sepsis, but its molecular mechanisms are not fully understood. Hydrogen sulfide (H₂S), an endogenous signaling molecule, regulates inflammation, oxidative stress, and cell death in cardiovascular diseases, with protein sulfhydration as a key mechanism.

We used in vitro and in vivo sepsis models we investigated the protective to examine the effects of H₂S donors (GYY4137 and Allicin) on SIMI. We focused on ferroptosis and the HIF1α/BNIP3 axis, and applied transcriptomic, proteomic, and molecular biology approaches.

Sepsis suppressed the CSE/H₂S pathway, increasing ferroptosis and myocardial injury. Exogenous H₂S attenuated cardiac dysfunction, inflammation, and cell death. Mechanistically, H₂S promoted HSPA8 sulfhydration at Cys574, enhancing HIF1α degradation and inhibiting BNIP3, thereby reducing oxidative stress, ferroptosis, and myocardial damage. Allicin, a natural H₂S donor, induced endogenous H₂S production, restored HSPA8 sulfhydration, and provided cardioprotection without toxicity.

This study reveals a novel H₂S-HSPA8-HIF1α-BNIP3 axis in regulating ferroptosis and myocardial injury during sepsis. Protein sulfhydration mediates the cardioprotective effects of H₂S, and Allicin emerges as a promising therapeutic agent for septic cardiomyopathy.