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

Ning An1,2, Yunjie Chen3, Lin Li1

  • 1The Affiliated Li Huili Hospital of Ningbo University, Health Science Center, Ningbo University, Ningbo, P.R. China.

Communications Biology
|November 25, 2025
PubMed

Insights

Fibroblast growth factor 9 (FGF9) protects against diabetic cardiomyopathy (DCM) by activating Nrf2 signaling through AMPK and autophagy. This FGF9 mechanism improves cardiac function and reduces injury in diabetic hearts.

Area of Science:

  • Cardiology
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetic cardiomyopathy (DCM) is a significant complication of diabetes, characterized by cardiac dysfunction.
  • The role of Fibroblast Growth Factor 9 (FGF9) in DCM pathogenesis is not well understood.
  • Existing research highlights FGF9's importance in development and cardioprotection.

Purpose of the Study:

  • To investigate the therapeutic potential of FGF9 in a preclinical model of DCM.
  • To elucidate the underlying molecular mechanisms by which FGF9 exerts its effects in DCM.
  • To explore the interplay between FGF9, AMPK, autophagy, and Nrf2 signaling in the diabetic heart.

Main Methods:

  • A high-fat diet/streptozotocin (HFD/STZ) induced DCM mouse model was utilized.
  • Cardiomyocyte-specific Nrf2 knockout mice were employed to assess Nrf2 dependency.
  • Neonatal rat cardiomyocytes (NRCMs) were treated with high glucose and palmitate (HG+PA).
  • Adeno-associated virus (AAV9) mediated gene delivery was used to modulate AMPK activity.

Main Results:

  • FGF9 treatment attenuated cardiac hypertrophy, fibrosis, and systolic dysfunction in HFD/STZ mice.
  • These protective effects were abolished in cardiomyocyte-specific Nrf2 knockout mice, indicating Nrf2 dependence.
  • FGF9 restored AMPK activity, promoted autophagy, and enhanced p62-mediated Keap1 degradation, leading to Nrf2 nuclear translocation.
  • In NRCMs, FGF9 reversed HG+PA-induced suppression of AMPK, autophagy, and Nrf2 signaling.
  • AMPK activation was confirmed as essential for FGF9-induced Nrf2 activation.
  • FGF9 reduced lipid accumulation, preserved mitochondrial integrity, and alleviated oxidative stress in the diabetic heart.

Conclusions:

  • FGF9 ameliorates DCM through a non-canonical autophagy-dependent activation of Nrf2, mediated by AMPK.
  • FGF9 demonstrates significant cardioprotective effects in diabetic myocardial injury.
  • FGF9 represents a promising therapeutic target for managing diabetic cardiomyopathy.

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