Work

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

Year: 2025

Type: article

Abstract: BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Source: Arthritis Research & Therapy

DOI: 10.1186/s13075-025-03715-4