Cardiac hypertrophy is a major contributor to heart failure, yet therapeutic options remain limited. Emerging evidence suggests that upregulated expression of histone lysine-specific demethylase 4A (KDM4A) in patients with cardiac hypertrophy may represent a significant, albeit underappreciated, disease risk factor; however, the underlying mechanism and specific downstream pathway remain unclear. In this study, we investigated the therapeutic effect of SD49-7, a specific KDM4A inhibitor, on cardiac hypertrophy and its underlying mechanism, utilizing both in vivo and in vitro models. Employed isoprenaline (ISO)-induced mouse model of cardiac hypertrophy in vivo, and stimulated rat cardiomyocytes (H9c2 cells) with ISO, phenylephrine (PE), angiotensin II (Ang II) in vitro. Echocardiography, histopathology analysis and serological indicators demonstrated that SD49-7 treatment significantly alleviated cardiac hypertrophy in ISO-treated mice. Furthermore, SD49-7 significantly inhibited the expression levels of hypertrophy markers ANP, BNP and β-MHC in stimulated H9c2 cells. Mechanistically, ATAC-seq results from mouse hearts revealed that the amelioration effects of SD49-7 on cardiac hypertrophy depend on S100B upregulation via KDM4A inhibition. Conversely, suppression of S100B expression in cardiomyocytes abolished the protective effects of SD49-7 against hypertrophy. In conclusion, our findings demonstrate that SD49-7 upregulates S100B expression in cardiomyocytes in a KDM4A-dependent manner, which in turn ameliorates the cardiac hypertrophic phenotypes. These results suggest that SD49-7 represents a promising therapeutic strategy for cardiac hypertrophy.
