Hyperoside Alleviates Myocardial Fibrosis by Reducing Oxidative Stress via the GATA4/HIF-1α Pathway in Mice

Background/Objective: Myocardial fibrosis (MF) is a prevalent pathological endpoint in various heart diseases, characterized by extracellular matrix (ECM) dysregulation and oxidative stress. Hyperoside (Hyp) plays a role in regulating cardiac oxidative stress and fibrosis. This study aimed to elucidate whether Hyp regulates isoproterenol (ISO)-induced MF in mice by modulating the GATA4/HIF-1α signaling pathway and reducing oxidative stress. Methods: The binding affinity of Hyp to GATA4 and HIF-1α was assessed through molecular docking and dynamics simulation. The MF model of mice was established by subcutaneous injection of ISO. Cardiac function was measured by echocardiography. Myocardial injury and collagen deposition were examined using H&E and Sirius red staining. Levels of fibrosis markers, oxidative stress indicators, and GATA4/HIF-1α pathway indicators in serum and heart tissue were quantified by ELISA, Western blot, RT-qPCR and flow cytometry. The distribution of myocardial marker proteins was visualized by immunofluorescence and immunohistochemistry. Results: Molecular docking revealed high binding affinity of Hyp to GATA4 and HIF-1α (binding energies < −5.0 kcal·mol−1), and dynamics simulation showed that the complex’s structure remained stable over 100 nanoseconds (RMSD < 0.1 nm). High-dose Hyp (36 mg/kg) significantly improved cardiac function, myocardial injury, collagen deposition, and inflammatory infiltration in MF mice. Molecularly, Hyp effectively reduces oxidative stress and fibrosis through upregulating GATA4 and downregulating HIF-1α. Conclusions: Hyp suppresses oxidative stress by activating the GATA4/HIF-1α pathway, presenting a promising therapeutic target for the treatment of MF.