Disarming cGAS-STING hyperactivation in autoimmune and inflammatory diseases: Pathogenic mechanisms and emerging therapeutic strategies

Aberrant activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been increasingly recognized as a key driver of autoimmune and inflammatory diseases. In recent years, accumulating evidence has highlighted the close association between cGAS-STING signaling and the pathogenesis of these disorders, suggesting that pharmacological targeting of this pathway may represent a promising therapeutic strategy. This review provides a comprehensive overview of the molecular mechanisms underlying cGAS-STING hyperactivation and its pathological roles across diverse diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), non-alcoholic steatohepatitis (NASH), STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, Niemann-Pick disease type C (NPC), neurodegenerative diseases and cancer. We critically evaluate current and emerging pharmacological strategies targeting the cGAS-STING pathway, encompassing direct cGAS and STING inhibitors, protein degradation technologies, epigenetic modulation, regulation of biomolecular phase separation, and artificial intelligence (AI)-enabled drug discovery approaches. By integrating disease-specific pathogenic mechanisms with therapeutic opportunities, this review highlights key challenges and future directions in the development of cGAS-STING-targeted therapies. Collectively, these insights provide a translational perspective for precision targeting of pathological cGAS-STING activation.