USP7 Regulates TRPV1 Deubiquitination to Mediate Chondrocyte Ferroptosis and Alleviate Osteoarthritis

ABSTRACT Osteoarthritis (OA) is a common degenerative joint disease characterized by chondrocyte dysfunction. In this study, we explored the function and mechanism of ubiquitin‐specific protease 7 (USP7) in chondrocyte ferroptosis in OA. The USP7, TRPV1, collagen II, and GPX4 levels in knee joint tissue were detected using immunohistochemistry. Safranin O‐Fast Green staining detected histopathological changes in OA mice. RT‐qPCR and western blotting determined the expression of USP, TRPV1, collagen II, iNOS, MMP13, and MMP3. Primary mouse chondrocytes were treated with IL‐1β in vitro to simulate OA. Chondrocyte viability was assessed using the MTT assay. Immunofluorescence staining revealed an increase in reactive oxygen species levels. MDA and Fe 2+ levels were measured using appropriate kits. The interaction between USP and TRPV1 was detected using co‐immunoprecipitation. An immunoprecipitation assay was used to evaluate TRPV1 ubiquitination. USP7 expression was downregulated in OA mice and IL‐1β‐stimulated chondrocytes. USP7 overexpression inhibited IL‐1β‐stimulated ferroptosis and extracellular matrix (ECM) degradation in chondrocytes. USP7, a deubiquitinating enzyme for TRPV1, enhanced TRPV1 stability Reinforced TRPV1 suppressed IL‐1β‐triggered chondrocyte ferroptosis and ECM degradation. Silencing TRPV1 reversed the effect of USP7 upregulation on IL‐1β‐induced chondrocyte ferroptosis and OA in OA mice. Therefore, USP7 protects chondrocytes from ferroptosis and ameliorates OA progression by deubiquitinating and upregulating TRPV1, thus providing a new therapeutic target for OA treatment.