Dual modulation of atherosclerosis by exercise and metformin: convergent pathways, divergent outcomes, and therapeutic potential.

Atherosclerosis remains a major contributor to cardiovascular morbidity and mortality, characterized by endothelial dysfunction, chronic inflammation, and metabolic dysregulation. Both exercise and metformin have demonstrated cardiovascular benefits through overlapping molecular mechanisms, notably involving AMP-activated protein kinase (AMPK) activation, mitochondrial biogenesis, anti-inflammatory pathways, and autophagy regulation. This review synthesizes current evidence on how these 2 interventions individually and jointly modulate vascular remodeling and atherogenesis. We critically examine their synergistic effects and potential conflicts, particularly regarding AMPK signaling intensity, tissue-specific responsiveness, and the influence of intervention timing, dose, and host metabolic state. We also explore how exercise and metformin interact dynamically across key molecular networks, including the M3-calcium/calmodulin-dependent protein kinase kinase beta-AMPK axis and downstream effectors such as sirtuin 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. While emerging data suggest potential benefits from the combined intervention in attenuating vascular aging and plaque formation, evidence remains mixed, and context-dependent responses are increasingly recognized. This review highlights the need for individualized intervention strategies and proposes mechanistic models to guide future research. Overall, a deeper understanding of the dynamic crosstalk between exercise and metformin may enhance the development of personalized therapies for atherosclerotic cardiovascular disease.