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Background <p>Diabetic cardiomyopathy (DCM) is characterized by oxidative stress and a critical loss of myocardial metabolic flexibility, yet therapies targeting these intrinsic disease drivers remain limited. We investigated whether cardiac-restricted activation of nuclear factor erythroid 2-related factor 2 (Nrf2) protects against DCM by orchestrating metabolic rewiring beyond its canonical antioxidant role.</p> Methods <p>This study integrated human bulk and single-nucleus transcriptomics with a cardiomyocyte-specific Nrf2 gain-of-function mouse model subjected to streptozotocin (STZ)-induced diabetes.</p> Results <p>Human transcriptomic analysis revealed that Nrf2 suppression is a hallmark of the DCM gene signature and correlates with mitochondrial dysfunction. In vivo, cardiomyocyte-restricted Nrf2 overexpression significantly attenuated diabetes-induced systolic and diastolic dysfunction, preventing ventricular dilation and myocardial fibrosis. At the single-cell level, Nrf2 activation preserved sarcomere shortening kinetics and mitochondrial respiration while reducing oxidative injury. Mechanistically, Nrf2 prevented the metabolic collapse typical of diabetic hearts by sustaining two parallel signaling axes: it restored Akt phosphorylation to maintain glycolytic competence and preserved AMPK-PGC-1α signaling to support fatty acid oxidation (FAO) capacity. Crucially, pharmacological inhibition of PI3K/Akt or AMPK abolished the Nrf2-mediated preservation of glycolysis and FAO, respectively, confirming that Nrf2 confers protection through this coordinated metabolic regulation.</p> Conclusion <p>These findings identify a novel Nrf2–Akt–AMPK–PGC-1α signaling axis that safeguards the heart against diabetic injury. By re-establishing metabolic flexibility and redox homeostasis, cardiomyocyte-restricted Nrf2 activation represents a potential disease-modifying strategy for DCM.</p>

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Cardiac-restricted Nrf2 activation blocks diabetic cardiomyopathy via Akt-driven glycolysis and AMPK-PGC-1α fatty-acid oxidation

  • 期刊论文

  • 发表日期：

    2026年2月18日

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  • Ying Jiang,
  • Dayun Tao,
  • Zhiyu Jin,
  • Zunyan Li,
  • Xiuling He,
  • Hao Zhou,
  • Hang Zhu,
  • Lina Ren

摘要

Background

Diabetic cardiomyopathy (DCM) is characterized by oxidative stress and a critical loss of myocardial metabolic flexibility, yet therapies targeting these intrinsic disease drivers remain limited. We investigated whether cardiac-restricted activation of nuclear factor erythroid 2-related factor 2 (Nrf2) protects against DCM by orchestrating metabolic rewiring beyond its canonical antioxidant role.

Methods

This study integrated human bulk and single-nucleus transcriptomics with a cardiomyocyte-specific Nrf2 gain-of-function mouse model subjected to streptozotocin (STZ)-induced diabetes.

Results

Human transcriptomic analysis revealed that Nrf2 suppression is a hallmark of the DCM gene signature and correlates with mitochondrial dysfunction. In vivo, cardiomyocyte-restricted Nrf2 overexpression significantly attenuated diabetes-induced systolic and diastolic dysfunction, preventing ventricular dilation and myocardial fibrosis. At the single-cell level, Nrf2 activation preserved sarcomere shortening kinetics and mitochondrial respiration while reducing oxidative injury. Mechanistically, Nrf2 prevented the metabolic collapse typical of diabetic hearts by sustaining two parallel signaling axes: it restored Akt phosphorylation to maintain glycolytic competence and preserved AMPK-PGC-1α signaling to support fatty acid oxidation (FAO) capacity. Crucially, pharmacological inhibition of PI3K/Akt or AMPK abolished the Nrf2-mediated preservation of glycolysis and FAO, respectively, confirming that Nrf2 confers protection through this coordinated metabolic regulation.

Conclusion

These findings identify a novel Nrf2–Akt–AMPK–PGC-1α signaling axis that safeguards the heart against diabetic injury. By re-establishing metabolic flexibility and redox homeostasis, cardiomyocyte-restricted Nrf2 activation represents a potential disease-modifying strategy for DCM.