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

ABSTRACT

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.