Deubiquitinases as Regulators and Therapeutic Targets in Vascular Diseases

Ubiquitination and deubiquitination are dynamic post-translational regulatory processes that control protein stability and signaling. Deubiquitinases (DUBs), which remove ubiquitin chains from target proteins, have emerged as important regulators of vascular homeostasis and disease. In this review, we summarize recent progress in defining the roles of DUBs in major vascular pathologies, including vascular inflammation, remodeling, neointimal formation, angiogenesis, endothelial barrier dysfunction, thrombosis, and fibrosis. Accumulating evidence indicates that distinct DUBs act in a cell type- and context-dependent manner in endothelial cells, vascular smooth muscle cells, immune cells, and fibroblasts, contributing to vascular diseases such as aortic aneurysm, atherosclerosis, pulmonary hypertension, ischemic stroke, and intimal hyperplasia. These findings support DUBs as key regulatory nodes integrating ubiquitin signaling with inflammatory and stress-response pathways in the vasculature. In parallel, efforts to pharmacologically modulate DUB activity have led to the development of selective inhibitors and activators, although challenges remain in achieving substrate specificity and tissue selectivity. Overall, DUBs represent promising therapeutic targets for vascular disease, and future studies should focus on defining disease-specific DUB-substrate networks and developing context-dependent strategies for precise vascular intervention.