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<p>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 <i>Nrf2</i> 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 (<i>AMPK</i><sup><i>WT</i></sup>) or a dominant-negative AMPK mutant (<i>AMPK</i><sup><i>T172A</i></sup>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Ning An,
  • Yunjie Chen,
  • Lin Li,
  • Bingyu Wang,
  • Xuan Zhou,
  • Gen Chen

摘要

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 (AMPKWT) or a dominant-negative AMPK mutant (AMPKT172A) 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.