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Inflammatory bowel diseases (IBDs) are increasingly common diseases characterized by chronic and relapsing inflammation of the gastrointestinal tract. NLRP3 might be a crucial regulator of the homeostatic balance of the intestine, but its upregulation leads to pyroptosis. Munronoid I is extracted and purified from Munronia sinica, which has shown an anti-inflammatory effect, but the efficacy of Munronoid I in IBD remains unproven. In this study, we attempted to determine the effect of Munronoid I on NLRP3 to regulate the inflammasome activation and pyroptosis in IBD. Our data demonstrated that Munronoid I treatment attenuated DSS-induced body weight loss, pathological injury of the colon, the production of IL-1β and IL-18, and the expression of pyroptosis-associated proteins in colon tissue in mice. Moreover, Munronoid I inhibited LPS/ATP-induced pyroptosis in mouse peritoneal macrophages, MODE-K cells, and DSS-induced pyroptosis in mouse colonic epithelial cells, and decreased the release of inflammatory cytokines IL-1β and IL-18 in mouse peritoneal macrophages. Mechanically, Munronoid I could suppress the NLRP3 inflammasome activation and pyroptosis by promoting the K48-linked ubiquitination and NLRP3 degradation. It is suggested that Munronoid I might be a potential therapeutic candidate for IBD.