Targeting IRAK4 mitigates osteoarthritis by preserving mitochondrial homeostasis and suppressing MAPK/NF-κB-mediated inflammation

Osteoarthritis (OA), a prevalent and debilitating condition driven by progressive cartilage degeneration, represents a significant global health challenge due to the absence of effective disease-modifying therapies. Interleukin-1 receptor-associated kinase 4 (IRAK4), a key signaling kinase at the nexus of innate and adaptive immunity, has emerged as a promising therapeutic target for inflammatory diseases. This study elucidates the critical role of IRAK4 in OA pathogenesis. We found IRAK4 expression was significantly upregulated in both osteoarthritic cartilage and IL-1β-stimulated primary chondrocytes. Genetic silencing or pharmacological inhibition with the clinical-stage compound PF-06650833 effectively ameliorated IL-1β-induced inflammatory responses, extracellular matrix degradation, cellular senescence, and mitochondrial dysfunction. Mechanistically, we demonstrated that IRAK4 drives these catabolic processes by activating the MAPK/NF-κB signaling pathway through the TRAF6-TAK1 complex, a process further amplified by METTL3. Crucially, in a rat model of post-traumatic OA induced by DMM, intra-articular injection of an adeno-associated virus carrying shIRAK4 to knock down IRAK4 successfully attenuated overall disease progression, as evidenced by significantly reduced cartilage erosion, osteophyte formation, and aberrant subchondral bone remodeling. Our findings collectively establish IRAK4 as a central driver of OA pathology and highlight the strong translational potential of therapeutic IRAK4 inhibition, exemplified by PF-06650833, as a novel disease-modifying strategy.