Vascular smooth muscle cell metabolic reprogramming and phenotypic remodeling in atherosclerosis

Abstract Metabolic reprogramming of vascular smooth muscle cells (VSMC) is emerging as a central driver of atherosclerotic plaque heterogeneity and instability. VSMCs undergo phenotypic remodeling into osteogenic, macrophage-like, foam cell–like, or pro-inflammatory states through metabolic reprogramming, which actively drives vascular calcification, lipid accumulation, and extracellular matrix degradation. In this review, we summarize the various phenotypes of VSMCs observed during AS development and describe potential molecular pathways linking metabolic reprogramming to phenotypic remodeling. We highlight key regulators, including glucose transporters, pyruvate dehydrogenase kinase 4, 6 - Phosphofructo - 2 - kinase/fructose - 2, 6 - bisphosphatase 3, pyruvate kinase M2, fatty acid synthase, homocysteine, etc., which integrate extracellular stimuli and intracellular metabolic changes to drive VSMCs fate decisions. In addition, we discuss how specific metabolic pathways interact with epigenetic and signaling networks to regulate VSMCs proliferation, apoptosis, calcification, foaming, and aging. Finally, we explore therapeutic opportunities for targeted metabolic regulators, including traditional Chinese medicine, Sirtuin 1 activators, ATP-Citrate Lyase inhibitors, statins, folic acid, etc., providing new strategies to stabilize plaques and slow the progression of AS.