Epigenetic dysregulation of energy homeostasis drives aortic valve stenosis that is treatable with metformin.

Aortic valve stenosis is a progressive and increasingly prevalent disease in older adults, with no approved pharmacologic therapies to prevent or slow its progression. Although genetic risk factors have been identified, the contribution of epigenetic regulation remains poorly understood. Here, we demonstrated that histone deacetylase 3 (HDAC3) maintains aortic valve structure by suppressing mitochondrial biogenesis and preserving extracellular matrix integrity in valvular interstitial fibroblasts. Human stenotic valves displayed elevated acetylation of histone H3 at lysine 27 (H3K27ac) and reduced HDAC3 activity in diseased regions. Mice lacking HDAC3 in aortic valves developed aortic valve stenosis, disrupted collagen organization, increased H3K27ac, and premature mortality. Mechanistically, HDAC3 loss led to activation of nuclear hormone receptor-regulated mitochondrial gene programs, increased oxidative phosphorylation, and reactive oxygen species-induced damage. Treatment with metformin, a mitochondrial complex I inhibitor, restored redox balance, preserved collagen structure, and improved valve function in Hdac3-deficient mice. Supporting these experimental findings, retrospective clinical analysis revealed a significantly lower prevalence and slower progression of aortic valve stenosis in patients treated with metformin. These results uncovered a potentially previously unrecognized role for HDAC3 in coordinating epigenetic and metabolic homeostasis in the aortic valve, suggesting that targeting mitochondrial dysfunction may offer a therapeutic strategy for noncalcific aortic valve disease.