Rayan Arzouni, Reem Aazar, Seif Asakrieh, Seif Cattan, Aleksandar Jovanović
Heart failure (HF) is a complex clinical syndrome characterized not only by impaired cardiac function but also by profound disturbances in myocardial energy metabolism. AMP-activated protein kinase (AMPK), a central cellular energy sensor, plays a critical role in maintaining metabolic homeostasis by coordinating pathways involved in substrate utilization, mitochondrial function, autophagy, and stress adaptation. Experimental evidence supports a cardioprotective role of AMPK activation, including improved energetic efficiency, attenuation of pathological remodeling, and enhanced cellular resilience. However, emerging data indicate that AMPK signaling is highly context-dependent, with its effects varying according to HF phenotype, disease stage, and isoform-specific activity. While indirect AMPK modulation through established therapies such as metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors has demonstrated clinical benefit, the specific contribution of AMPK to these effects remains incompletely defined. Furthermore, direct pharmacological activation is limited by challenges including tissue specificity, off-target effects, and potential adverse outcomes associated with sustained activation. This review provides a comprehensive overview of AMPK signaling in HF, focusing on its role in metabolic remodeling, mitochondrial regulation, and interaction with key cardioprotective pathways. We also examine current clinical and translational evidence and discuss emerging strategies aimed at achieving isoform-selective and tissue-specific modulation. Collectively, these insights support a shift from broad AMPK activation toward precision-based therapeutic approaches tailored to the disease context.