Sevoflurane Alleviates Myocardial Ischemia‐Reperfusion Injury via the HMGB1/ACSL4 Pathway to Suppress Ferroptosis

Abstract

Sevoflurane (sevo) exhibits cardioprotective effects against myocardial ischemia/reperfusion injury (MIRI); however, its precise molecular mechanism of action remains elusive and warrants further in‐depth investigation. A rat model of MIRI and a hypoxia/reoxygenation (H/R) model in the H9c2 cardiomyocytes were established separately, followed by sevo treatment. Hematoxylin‐eosin staining, Perls staining, transmission electron microscope, FerroOrange staining, and Liperfluo staining were used to assess myocardial pathological damage, iron deposition, and oxidative stress. The contents of malondialdehyde, glutathione, Fe2+, and NADP + /NADPH were examined via relevant kits. Western blot, co‐immunoprecipitation, and immunofluorescence staining assays were employed to verify the interaction between high mobility group box 1 (HMGB1) and acyl‐CoA synthetase long chain family member 4 (ACSL4). In the rat MIRI model, sevo treatment mitigated myocardial tissue damage, attenuated oxidative stress, suppressed Fe2+ accumulation, and downregulated the expression of HMGB1 and ACSL4. In the H9c2 cardiomyocyte H/R injury model, sevo treatment enhanced cell viability, reduced intracellular Fe2+ levels, and alleviated lipid peroxidation. HMGB1 interacted with ACSL4 to stabilize ACSL4 protein expression. Furthermore, HMGB1 overexpression promoted H/R‐induced injury and ferroptosis in cardiomyocytes, whereas sevo abrogated these effects. Sevo alleviates MIRI and H/R injury by suppressing the HMGB1/ACSL4 pathway to mitigate ferroptosis, providing a new theoretical basis for myocardial protection approaches.