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AMPK Signalling in Heart Failure: From Metabolic Sensor to Context-Dependent Therapeutic Target
Rayan Arzouni1, Reem Aazar1, Seif Asakrieh2
1Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia CY-1700, Cyprus.
Biomedicines
|June 26, 2026
Summary
AMP-activated protein kinase (AMPK) is crucial for heart failure (HF) metabolic regulation. Tailoring AMPK therapies to specific HF contexts, rather than broad activation, may improve treatment outcomes.
Area of Science:
- Cardiovascular Medicine
- Metabolic Regulation
- Molecular Cardiology
Background:
- Heart failure (HF) involves impaired cardiac function and disrupted myocardial energy metabolism.
- AMP-activated protein kinase (AMPK) is a key cellular energy sensor regulating metabolic homeostasis.
- AMPK activation shows cardioprotective effects, but its role in HF is context-dependent.
Purpose of the Study:
- To review the role of AMPK signaling in heart failure's metabolic remodeling and mitochondrial function.
- To examine the clinical and translational evidence of AMPK modulation in HF.
- To discuss emerging strategies for precise, isoform- and tissue-specific AMPK modulation.
Main Methods:
- Comprehensive literature review of AMPK signaling in heart failure.
- Analysis of experimental and clinical data on AMPK modulators (metformin, SGLT2 inhibitors).
- Discussion of challenges and future directions in pharmacological AMPK activation.
Main Results:
- AMPK plays a critical role in substrate utilization, mitochondrial function, and stress adaptation in HF.
- Indirect AMPK modulation via metformin and SGLT2 inhibitors shows clinical benefits in HF.
- Direct AMPK activation faces challenges with specificity, off-target effects, and sustained activation risks.
Conclusions:
- AMPK signaling is complex and context-dependent in heart failure.
- Current therapies indirectly modulate AMPK, but its specific contribution is not fully understood.
- Future therapeutic strategies should focus on precision-based, context-tailored AMPK modulation for HF.
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