Bergenin attenuates diabetic cardiomyopathy by inhibiting oxidative stress and ferroptosis through modulation of the YAP signaling axis

AIMS Diabetes mellitus-associated cardiac dysfunction arises from metabolic imbalance, oxidative stress, inflammation, maladaptive remodeling, and impaired cardiac performance. Bergenin (BER), a naturally occurring small molecule with antioxidant, anti-inflammatory, and metabolic regulatory properties, has shown therapeutic potential; however, its role in diabetic cardiomyopathy (DCM) remains unclear. This study investigated the cardioprotective effects of BER in DCM, with particular emphasis on oxidative stress, the Hippo-Yes-associated protein (YAP), and ferroptosis signaling axis. MATERIALS AND METHODS DCM was induced in rats using a high-fat diet combined with low-dose streptozotocin (STZ). Diabetic rats received BER (25 or 50 mg/kg/day) or empagliflozin (10 mg/kg/day). Cardiac function was evaluated by echocardiography, followed by histopathological and molecular analyses. To further investigate the underlying mechanisms, H9c2 cardiomyoblasts exposed to high glucose were used for in vitro assessment of oxidative stress, Hippo-YAP signaling, and ferroptosis-related markers. KEY FINDINGS In vivo, BER treatment significantly improved cardiac function, attenuated histopathological injury, and reduced cardiomyocyte hypertrophy and fibrosis in diabetic rats. Consistent with these findings, in vitro, BER reduced reactive oxygen species generation, restored mitochondrial integrity, and prevented high glucose-induced injury in H9c2 cells. Mechanistically, BER modulated YAP signaling and suppressed ferroptosis-related changes. YAP silencing attenuated the protective effects of BER, supporting a critical role for YAP in mediating its anti-ferroptotic effects. SIGNIFICANCE These findings demonstrate that BER exerts cardioprotective effects against diabetes-associated cardiac dysfunction and provide mechanistic evidence implicating the YAP-ferroptosis axis in this protection. Further studies are warranted to establish its translational potential.