FGF9 alleviates diabetic cardiomyopathy by activating Nrf2 via SQSTM1/p62-Keap1 in mice

Fibroblast growth factor 9 (FGF9) plays a key role in development and cardioprotection, yet its function in diabetic cardiomyopathy (DCM) remains unclear. In a high-fat diet/streptozotocin (HFD/STZ)-induced DCM model, FGF9 attenuated cardiac hypertrophy, fibrosis, and systolic dysfunction, effects abolished in cardiomyocyte-specific Nrf2 knockout mice. Mechanistically, FGF9 restored AMPK activity and promoted autophagy, enhancing p62-mediated degradation of Keap1 and nuclear translocation of Nrf2. In neonatal rat cardiomyocytes (NRCMs), FGF9 reversed high glucose and palmitate (HG + PA)-induced suppression of AMPK phosphorylation, autophagic flux, and Nrf2 signaling. AAV9-mediated expression of wild-type AMPK (AMPK^WT) or a dominant-negative AMPK mutant (AMPK^T172A) confirmed that AMPK activation was essential for FGF9-induced Nrf2 activation. Functionally, FGF9 reduced lipid accumulation, preserved mitochondrial integrity, and alleviated oxidative stress. FGF9 ameliorates DCM via non-canonical autophagy-dependent activation of Nrf2, mediated by AMPK. These findings position FGF9 as a potential therapeutic target for diabetic myocardial injury.