Sodium crotonate alleviates diabetic cardiomyopathy in association with enhanced histone H3K18 crotonylation

Diabetic cardiomyopathy (DCM) is a common and severe major complication of diabetes, and effective treatment strategies are currently lacking. Existing research indicates that protein post-translational modifications (PTMs) play a critical role in its pathophysiological mechanisms; however, the function of the emerging lysine crotonylation modification (Kcr) in DCM remains unclear. The results of this study show that both global lysine crotonylation and histone H3K18 crotonylation (H3K18cr) levels are elevated in heart tissues of DCM models, as well as in AC16 cells induced by high glucose and palmitic acid. Supplementation with sodium crotonate (NaCr) further increased histone crotonylation and H3K18cr, and was associated with reduced cardiac inflammation, fibrosis, and injury under DCM conditions. Moreover, the NaCr‑induced H3K18cr and its protective effects were reversed by inhibiting acetyl-CoA synthetase 2 (ACSS2) in vitro. Taken together, these findings reveal an association between NaCr-enhanced H3K18cr and attenuation of DCM phenotypes. While H3K18cr may represent a potential correlate of cardioprotection, its direct causal role and the possible confounding effect of NaCr’s glucose-lowering activity remain to be clarified by future studies.