BRD4 inhibition ameliorates aberrant mechanical stress-induced temporomandibular joint osteoarthritis through modulating MLKL and necroptosis.

This study aimed to investigate the role and underlying mechanisms of BRD4 in temporomandibular joint osteoarthritis (TMJOA) and to evaluate the therapeutic potential of its inhibitor, JQ1. A rat model of TMJOA was established through mechanical stress induction, and the protective effects of BRD4 inhibition were assessed via intra-articular injection of JQ1. In vitro, a chondrocyte necroptosis model was induced using TNF-α, Smac mimetic, and z-VAD-FMK (TSZ). Cell viability and necroptosis were evaluated using CCK-8, LDH release assays, flow cytometry, and immunofluorescence staining. BRD4 expression was notably upregulated in TMJ tissues subjected to aberrant mechanical stress. Inhibition of BRD4 by JQ1 exerted a protective effect and attenuated TMJOA progression. Mechanistically, BRD4 was found to regulate chondrocyte necroptosis and showed a positive correlation with the expression of RIP3 and MLKL. Chromatin immunoprecipitation revealed BRD4 enrichment at the MLKL promoter region. Both BRD4 knockdown and JQ1 treatment markedly reduced chondrocyte death and downregulated the expression of TNF-α, RIP3, MLKL, and p-MLKL. In summary, BRD4 overexpression contributes to the pathogenesis of TMJOA. Inhibition of BRD4 suppresses MLKL expression, thereby reducing chondrocyte necroptosis and alleviating TMJOA-associated pathological changes. These findings suggest that JQ1 and other BRD4-targeting strategies may represent promising therapeutic approaches for TMJOA.