Interleukin‐38 attenuates Obesity-induced cardiomyopathy through AMPK/autophagy‐mediated suppression of endoplasmic reticulum stress

Obesity-induced cardiomyopathy involves cardiac hypertrophy, apoptosis, and fibrosis, contributing to cardiac dysfunction. Autophagy activation alleviates endoplasmic reticulum stress (ERS). Interleukin (IL)-38, an IL-1 family cytokine with anti-inflammatory and metabolic regulatory properties, protects against cardiovascular diseases. This study investigated whether IL-38 attenuates obesity-induced cardiomyopathy by activating the AMP-activated protein kinase (AMPK)/autophagy pathway to suppress ERS. Mice fed a high-fat diet (HFD) for 20 weeks received IL-38 for the final 8 weeks, with or without an autophagy inhibitor. Cardiac function, serum metabolic parameters, myocardial histology, cardiomyocyte hypertrophy, and apoptosis were assessed. Autophagy and ERS-related proteins and their upstream signaling were evaluated by Western blotting. Primary cardiomyocytes were used for in vitro validation. IL-38 treatment significantly ameliorated myocardial injury in HFD-fed mice and palmitate-treated cardiomyocytes. HFD-suppressed autophagy was restored by IL-38, while elevated ERS was markedly attenuated. The cardioprotection and ERS alleviation conferred by IL-38 were autophagy-dependent and mediated specifically through the AMPK/autophagy signaling pathway; inhibition of either autophagy or AMPK abolished these protective effects. These direct myocardial benefits were accompanied by improved systemic metabolic parameters and reduced cardiac inflammatory cytokines. In conclusion, IL-38 ameliorates obesity-induced cardiomyopathy primarily by activating AMPK/autophagy signaling to alleviate ERS, with concurrent metabolic and anti-inflammatory benefits, highlighting its potential as a therapeutic candidate.