Deubiquitinating Enzymes in Osteoarthritis: From Mechanisms to Therapeutic

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage erosion, synovial inflammation and pain. Accumulating evidence demonstrates that deubiquitinating enzymes (DUBs) are critical regulators of OA pathogenesis through their ability to rescue key proteins from proteasomal degradation. Among them, USP7 stabilizes NOX4 to amplify ROS-NLRP3-dependent pyroptosis and cartilage catabolism; USP15 deubiquitinates ERK2 and SMAD2 to enhance TGF-β signaling and chondrocyte anabolism; USP13 sustains PTEN and IL-1R8/Sigirr to restrain PI3K/AKT/NF-κB-mediated inflammation and oxidative stress; USP3 and USP49 block TRAF6 ubiquitination and Wnt/β-catenin signaling to attenuate chondrocyte senescence and apoptosis; USP5 and USP14 promote NF-κB activation by stabilizing TRAF6 or deubiquitinating IκBα, driving chondrocyte dedifferentiation and matrix metalloproteinase expression. Pre-clinically, small-molecule USP7 inhibitors (P22077), USP14 inhibitors (IU1) and genetic silencing of USP15 or USP49 have all been shown to reduce cartilage loss and inflammatory pain in mouse OA models. Collectively, these findings establish DUBs as druggable nodes in OA and underscore the need for selective inhibitors that can safely modulate ubiquitin-dependent protein turnover in human joints.However, DUB research remains nascent, requiring further validation of their clinical efficacy and safety. This review elucidates DUB-mediated mechanisms in OA and discusses challenges in developing selective DUB inhibitors for future therapies.