Metabolic Milieu and Susceptibility: The Combined Benefits of Targeting AMPK and ACE2 for Metabolic Disorders and COVID-19.

The convergence of metabolic dysfunction and infectious diseases has become increasingly evident, particularly during the COVID-19 pandemic. AMP-activated protein kinase (AMPK) and angiotensin-converting enzyme 2 (ACE2) emerge as pivotal molecular regulators linking metabolic homeostasis, endothelial integrity, immune modulation, and viral pathogenesis. Metabolic diseases such as diabetes, obesity, and non-alcoholic fatty liver disease are marked by insulin resistance, chronic inflammation, oxidative stress, and endothelial dysfunction, collectively increasing susceptibility to severe viral infections and outcomes. This review examines experimental, computational, and translational evidence exploring the interplay between AMPK and ACE2, focusing on metabolic, vascular, and inflammatory pathways relevant to viral infections. Recent findings show a bidirectional functional relationship between AMPK and ACE2, where AMPK phosphorylation supports ACE2 expression and function, and ACE2 signaling reciprocally enhances AMPK activity, forming a protective metabolic-vascular loop. Disruption of this axis, particularly through SARS-CoV-2-induced ACE2 degradation, exacerbates metabolic deterioration, vascular damage, and exaggerated inflammatory responses. Preclinical and in silico studies show that pharmacological AMPK activators, including metformin and bioactive flavonoids, demonstrate pleiotropic metabolic, anti-inflammatory, endothelial protective, and potential antiviral activities, hinting at the therapeutic potential of modulating the AMPK-ACE2 axis, despite the limited clinical application of flavonoids. The AMPK-ACE2 axis represents an important molecular link between metabolic regulation, renovascular health, and immune defense mechanisms. This evaluation connects AMPK and ACE2 from isolated signaling nodes into a coordinated pharmacological axis with implications for interventions in cardiometabolic and viral diseases. Future research should prioritize mechanistic validation and conduct integrated experimental and clinical investigations to establish AMPK-ACE2 co-targeting as a viable therapeutic strategy for mitigating cardiometabolic disease burden and enhancing resilience against viral infections.