The role of the cGAS-STING-mediated inflammatory amplification loop in osteoarthritis: from danger-associated DNA sensing to whole-joint remodeling and precision therapy

Osteoarthritis (OA) is a heterogeneous disorder of the entire joint in which mechanical overload, aging, metabolic disturbance, and dysregulated immunity converge. Growing evidence places the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) pathway at the interface between cellular damage and sterile inflammation because this pathway detects self-deoxyribonucleic acid (DNA) that escapes its normal intracellular compartments. This review interprets current findings through a danger-signal amplification framework rather than treating cGAS–STING as an isolated inflammatory pathway. Mechanical and metabolic stress, oxidative injury, and aging can compromise mitochondrial and nuclear integrity; among the resulting DNA species, cytosolic mitochondrial DNA (mtDNA) currently has the strongest experimental support as an endogenous activator of cGAS in OA. cGAS-generated 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) activates STING and engages TANK-binding kinase 1 (TBK1)–interferon regulatory factor 3 (IRF3)/type I interferon (IFN-I) and nuclear factor kappa B (NF-κB) programs. These responses intersect with inflammasomes, pyroptosis, cellular senescence, and the senescence-associated secretory phenotype (SASP), thereby linking DNA exposure to renewed tissue injury. Extracellular vesicles (EVs), including vesicles carrying mtDNA, can extend this process across cartilage, synovium, the infrapatellar fat pad, and subchondral bone and help convert focal cellular stress into whole-joint remodeling. Potential interventions therefore span several levels: preventing mtDNA damage or escape, restoring mitochondrial quality control, directly modulating cGAS or STING, attenuating downstream inflammatory and cell-death programs, and improving tissue-selective local delivery. A major translational priority is to define when and in which OA endotypes cGAS–STING activity is sufficiently dominant to justify pathway-directed treatment. Combining temporal analysis, cell-specific models, and mechanism-linked biomarkers may ultimately support stage-adapted therapy that controls danger signals while preserving physiological innate immune function.