GSDMD protected against colitis through restricting cGAS-dependent inflammation.Cytosolic DNA-sensing pathway was upregulated in CD11b+F4/80+ cells in Gsdmd-/- mice, in which many genes were associated with cGAS, companied with higher levels of cGAMP in colon. Phosphorated-STING, p-TBK1 and p-IRF3 were increased in in the Gsdmd−/− colonic tissues compared with controls after DSS challenge. The intraperitoneal injection of cGAS inhibitor RU.521 alleviated intestinal colitis in Gsdmd−/− mice. The gene discussed is CGAS; the disease is colitis.