Aerobic Exercise Mitigates Experimental Knee Osteoarthritis via Inhibition of cGAS–STING Signaling

Knee osteoarthritis (KOA) is a chronic joint disorder characterized by cartilage deterioration. lacking disease-modifying therapies. Aerobic exercise is recommended as a first-line non-pharmacological intervention for KOA, but its molecular mechanisms remain unclear. Recent studies indicate that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a key regulator of inflammation and cartilage homeostasis, may mediate the protective effects of aerobic exercise on joint integrity. Male C57BL/6 mice underwent destabilization of the medial meniscus (DMM) surgery and were assigned to Sham, Aerobic exercise, DMM, and DMM + Aerobic exercise groups. Aerobic treadmill running was performed for 4 weeks, with a STING agonist (DMXAA) and STING inhibitor (C-176) used to verify pathway involvement. Joint function, cartilage histology, inflammatory cytokines, ECM metabolism, chondrocyte apoptosis, and cGAS-STING pathway activation, including phosphorylation levels and 2'3'-cGAMP production, were assessed. DMM induced joint swelling, gait impairment, cartilage degradation, ECM catabolism, chondrocyte apoptosis, inflammation, and robust cGAS-STING pathway activation. Aerobic exercise significantly ameliorated these changes, improving joint function, preserving cartilage and ECM integrity, reducing apoptosis, suppressing inflammatory cytokines, and directly inhibiting cGAS-STING signaling. STING inhibition alone exerted comparable chondroprotective effects to aerobic exercise, and no additional benefit was observed in combination. DMXAA treatment abolished these protective effects. Aerobic exercise alleviates DMM-induced knee osteoarthritis by enhancing joint function and preserving cartilage integrity, effects that are directly mediated through suppression of the cGAS-STING pathway. These findings establish a causal link between aerobic exercise and innate immune regulation in osteoarthritis.