Abstract

Purpose Myocardial fibrosis following myocardial infarction (MI) drives the progression of heart failure, yet effective therapeutic drugs remain unavailable. This study aimed to evaluate the anti-fibrotic effect of the natural small-molecule compound sennoside A (SA) on pathological fibrosis specifically at 28 days post-MI, and to explore its underlying molecular mechanism. Methods Mouse MI models were established and treated with SA for 28 days. To evaluate therapeutic efficacy, cardiac function was assessed by echocardiography, and myocardial fibrosis was quantified using histopathological staining. For mechanistic investigation, molecular docking and enzymatic activity assays were performed to determine whether SA targets the histone demethylase KDM4B. In vitro experiments were conducted to characterize the effects of SA on fibroblast activation and extracellular matrix production. Results SA significantly improved cardiac function, as reflected by increased left ventricular ejection fraction (LVEF) and fractional shortening (FS). Histological analysis showed that SA significantly reduced fibrotic area and collagen deposition compared with untreated MI mice. Mechanistically, molecular docking predicted a stable interaction between SA and KDM4B, and enzymatic assays confirmed that SA inhibited KDM4B activity and increased the modification of H3K9me3. Meanwhile, IRX2 expression was significantly downregulated, which was accompanied by reduced expression of fibrotic markers, extracellular matrix deposition and fibroblast phenotypic transformation. Conclusion This study identifies sennoside A binds to KDM4B and reduces the demethylase activity, thereby reducing IRX2 expression in a KDM4B-associated manner and ameliorating cardiac fibrosis after myocardial infarction and improving cardiac function. Graphical Sennoside A inhibits cardiac fibrosis by targeting the KDM4B/IRX2 signaling axis. SA can significantly down - regulate the expression of histone demethylase K