USP7 Regulates TRPV1 Deubiquitination to Mediate Chondrocyte Ferroptosis and Alleviate Osteoarthritis

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 Fe²⁺ 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.