Molecular mechanisms of aortic stenosis: Deciphering the role of cellular metabolism in the pursuit of novel therapeutic targets

Abstract Calcific aortic valve disease (CAVD), culminating in aortic stenosis (AS), is a progressive pathological condition marked by fibrocalcific remodeling of the aortic valve, for which no pharmacological therapies currently exist. Increasing evidence indicates that metabolic alteration of valvular cells is a central driver linking pathological stimuli to fibrocalcific changes. Hemodynamic stress, lipid infiltration, inflammation, and disturbed mineral balance synergistically induce metabolic shifts, characterized by augmented glycolysis, impaired oxidative phosphorylation, and oxidative stress. Beyond serving as a link between inflammation and calcification, metabolic intermediates such as acetyl-CoA and lactate act as epigenetic substrates, stabilizing osteogenic gene expression and perpetuating disease progression. The integration of metabolic and epigenetic signaling positions cellular metabolism as a nexus connecting pathogenic insults to calcification. Therapeutic strategies targeting glycolytic remodeling, mitochondrial dysfunction, and epigenetic modifications, combined with improved diagnostic imaging, physiologically relevant in vitro models, technological innovations, and the discovery of novel targets offer the promise of transforming CAVD management from late-stage surgical intervention to early prevention and precision medicine.