Targeting Cyclic GMP–AMP Synthase: Novel Therapeutic Inhibitors for Autoimmune Diseases

Cyclic GMP-AMP synthase (cGAS) is a crucial cytosolic DNA sensor in the innate immune system. Upon detecting intracellular double-stranded DNA (dsDNA), it activates the cGAS-STING signaling pathway, leading to the production of type I interferons and pro-inflammatory cytokines, which are essential for host defense against pathogens and antitumor immunity. However, persistent or aberrant activation of this pathway can trigger pathological immune responses, contributing to various autoimmune and inflammatory diseases. Consequently, the development of potent and specific cGAS inhibitors has emerged as a promising therapeutic strategy. This review comprehensively summarizes recent advances in cGAS inhibitor research. The article details the discovery, structural characteristics, mechanisms of action, structure-activity relationships, and preclinical efficacy of these inhibitors. It also discusses key challenges, such as species specificity and the disparity between biochemical and cellular potency. Finally, the review provides an outlook on future directions and the therapeutic potential of cGAS inhibitors.