USP32 promotes temporomandibular joint osteoarthritis by modulating PKM2 stability and glycolytic metabolism in chondrocytes

Metabolic alterations in chondrocytes play a crucial role in the progression of temporomandibular joint osteoarthritis (TMJOA). However, the precise molecular mechanisms underlying these changes remain poorly understood. In this study, we identify ubiquitin-specific protease 32 (USP32) as a key regulator of TMJOA progression through its interaction with pyruvate kinase M2 (PKM2), a vital enzyme in glycolysis. Our results demonstrate that USP32 is significantly upregulated in TMJOA cartilage and inflammatory chondrocytes. USP32 stabilizes PKM2 by removing K48- and K11-linked ubiquitin chains, thereby preventing its proteasomal degradation. This stabilization promotes the accumulation of PKM2, leading to enhanced glycolysis, increased lactate production, and mitochondrial dysfunction, all of which exacerbate chondrocyte apoptosis and the degradation of extracellular matrix. Knocking down USP32 or PKM2 mitigates these detrimental effects, restoring mitochondrial function and reducing inflammation. Furthermore, cartilage-specific knockdown of USP32 alleviates TMJOA pathology in a rat model, highlighting the therapeutic potential of targeting the USP32-PKM2 axis. Our findings reveal a novel mechanism through which USP32 regulates chondrocyte metabolism and inflammation via PKM2 deubiquitination, providing new insights into the pathogenesis of TMJOA and potential therapeutic strategies for its treatment.