cGAS/STING Signaling in Ulcerative Colitis: Mechanism and Therapeutic Opportunities

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by mucosal inflammation and epithelial barrier disruption. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, the principal cytosolic DNA-sensing axis, has emerged as a critical node in UC pathogenesis. This review elucidates the cGAS/STING signaling network in UC, from its upstream activation triggered by exogenous stimuli and leaked endogenous DNA to its downstream effects. We discuss how this pathway modulates distinct lines of intestinal defense, including the mechanical, chemical, and immunological barriers, while integrating its bidirectional crosstalk with the microbial barrier. Rather than exerting purely detrimental effects, cGAS/STING functions as a double-edged sword that coordinates both barrier homeostasis and inflammatory pathogenesis. Crucially, we summarize current pharmacological interventions, highlighting synthetic small molecules and bioactive natural products that target and modulate this axis to restore intestinal equilibrium. This framework provides a theoretical foundation for future precision therapies in UC.