RNF152-mediated, ubiquitin-dependent degradation of HSP27 activates the PI3K/AKT pathway, driving synovial inflammatory cascades in TMJOA

E3 ubiquitin ligases are established regulators of osteoarthritis pathogenesis known to amplify inflammatory signals via substrate protein destabilization, but their role in temporomandibular joint osteoarthritis (TMJOA) remains elusive. This study investigated the impact of E3 ligases on the activation of fibroblast-like synoviocytes (FLSs) in TMJOA and their mechanistic contributions to disease progression. High-throughput mRNA-sequencing identified dysregulated E3 ligases in interleukin-1β (IL-1β)–stimulated FLSs. Through integrated in vitro and in vivo analyses, we identified ring finger protein 152 (RNF152) as a key mediator of TMJOA pathogenesis. Comprehensive results from immunoprecipitation-mass spectrometry, co-immunoprecipitation, co-localization imaging, and protein docking demonstrated direct interaction between RNF152 and heat shock protein 27 (HSP27). IL-1β induced RNF152 upregulation while suppressing HSP27 expression in FLSs. Mechanistically, RNF152 ubiquitinated HSP27 at Lys114, making it a target for proteasomal degradation. Critically, RNF152-mediated HSP27 degradation activated the PI3K/AKT pathway, driving FLS proliferation and pro-inflammatory cytokine release, which accelerates TMJOA. Intra-articular delivery of adenovirus-associated virus-small interfering RNF152 attenuated synovial hyperplasia and chondrocyte damage in a rat model of TMJOA. This study elucidates the function of RNF152 as a novel E3 ligase and the dual regulatory role of HSP27 in inflammatory signaling. Importantly, our findings suggest that targeting the RNF152/HSP27/PI3K/AKT signaling axis may provide a novel therapeutic approach for TMJOA. Future research should focus on developing specific inhibitors to disrupt this pathway, thereby identifying promising therapeutic targets for targeted interventions in TMJOA.