Genistein improves heart failure with preserved ejection fraction through BNIP3L-mediated mitophagy

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular disorder, for which effective therapeutic strategies remain lacking. Mitochondrial dysfunction and impaired mitophagy are key mechanisms contributing to HFpEF. BNIP3L, a crucial receptor in mitochondrial autophagy, plays a significant role in maintaining cardiomyocyte energy balance. Here, we first report the therapeutic potential of genistein, a natural flavonoid, in treating HFpEF and its impact on BNIP3L-mediated mitophagy. HFpEF was induced in C57BL/6 mice through a high-fat diet (HFD) combined with Nω-nitro-L-arginine methyl ester (L-NAME). Mice and cardiomyocytes were treated with genistein, and heart function and pharmacological mechanisms was assessed. Genistein treatment significantly improved myocardial remodeling and heart function in HFpEF mice, as evidenced by improved echocardiographic parameters, blood pressure, and exercise performance. Histological analysis showed a reduction in myocardial damage, indicating genistein's protective effect. Mechanistically, Genistein directly interacts with BNIP3L protein, stabilizing its dimeric conformation and promoting its expression in cardiomyocytes. This interaction is critical for enhancing BNIP3L-mediated mitophagy. These findings suggest that genistein exerts a cardioprotective effect in HFpEF through BNIP3L-mediated mitophagy, positioning it as a promising therapeutic candidate for HFpEF.