Revisiting osteoarthritis pathogenesis through the lens of cGAS-STING: Mitochondrial damage, pyroptosis, and inflammatory cascades.

OA is no longer regarded as a purely "wear and tear" disease, but rather a multifactorial, low-grade inflammatory disease in which the innate immune pathway coordinates cartilage degeneration, synovitis, and abnormal subchondral bone remodeling. This article re-examines the pathogenesis of OA through the cGAS-STING pathway and its intersection with mitochondrial damage and pyroptosis. We summarized the evidence of mitochondrial dysfunction and mtDNA cytoplasmic escape induced by pathways such as mechanical overload, oxidative stress, and mitochondrial autophagy disorder. The leaked mtDNA activates the cGAS-STING pathway, thereby increasing the production of IFN-I and inflammatory cytokines. Meanwhile, mtDNA and reactive oxygen species provide initiation and activation signals for NLRP3 and AIM2 inflammasome, eventually leading to pyroptosis of cells. We propose a "multilevel coupling" hypothesis in which mtDNA leakage, cGAS-STING activation, and pyroptosis act as mutually reinforcing nodes that sustain sterile inflammation and accelerate OA progression, highlighting this axis as a promising target for disease-modifying therapy. The Translational Potential of this Article:This review outlines the mitochondrial damage-cGAS-STING-pyroptosis axis as a potential driver of OA, highlighting its role in sustaining chronic joint inflammation. By identifying key points for intervention: mitochondrial protection, cGAS-STING modulation, and inflammasome inhibition, this framework supports the development of targeted or combination therapies, offering a path toward disease-modifying treatments for OA.