By DoM Communications | Date published: November 17, 2025
Timothy Fitzgibbons, David McManus, Chinmay Trivedi, and Colleagues Study Epigenetic Dysregulation of Energy Homeostasis in Recent Publication
Aortic valve stenosis is a progressive and prevalent disease in older adults. With no approved pharmacologic therapies to prevent or slow down its progression, the topic remains poorly understood. In a recent study published in JCI Insight, Timothy Fitzgibbons, MD, PhD, associate professor of medicine in the Division of Cardiovascular Medicine, David McManus, MD, ScM, the Richard M. Haidack Professor of Medicine, chair, and professor of medicine in the Department of Medicine, Chinmay Trivedi, MD, PhD, professor of medicine in the Division of Cardiovascular Medicine, Sherin Saheera, postdoctoral researcher, and Ashley Blau, MD, Cardiology fellow, demonstrated that histone deacetylase 3 (HDAC3) maintains aortic valve structure by suppressing mitochondrial biogenesis and preserving extracellular matrix integrity in valvular interstitial fibroblasts. The team additionally found that 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.
Additional collaborators on the study included Timothy Cashman, MD, PhD, Edith Mensah Otabil, and Nouran Nagy.