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Purpose: The NLRP3 inflammasome is a substantial component of the inflammation process. The complex pathogenesis of and the implication of a vast number of components in the inflammasomeactivation pathway prompted us to search for compounds that have a wide therapeutic index and act at the level of multiple cellular targets. Although CRID3 blocks NLRP3 with high specificity in the laboratory, clinical trials of the compound reported weaker potency. Methods: We used NSC328382, a P2X7R antagonist, as an adjunctive therapy and generated a strategy to potentiate the effects of CRID3 in rats with DSS-induced colitis. Results: NSC328382/CRID3 combined therapy exhibited a significantly increased efficacy compared with either of the monotherapies. NSC328382/CRID3 was more efficient in 1) attenuating colon shortening and disease activity; 2) improving goblet cell density and both the macroscopic and microscopic scenario of the injured colon; 3) improving the antioxidant defense mechanisms of the inflamed colon against oxidative stress; and 4) mitigating the inflammation state by downregulating the proinflammatory cytokines. Pyroptotic cell death was also conspicuously restrained. Additionally, NSC328382 interrupted the MyD88/NF-κB axis. Moreover, NSC328382/CRID3 exhibited the ability to alter Th1/Th2 dominance. Conclusion:The clinical application of NSC328382/CRID3 may result in the generation of a novel approach for the treatment of IBDs.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology that increases the risk of developing colorectal cancer and imposes a lifelong healthcare burden on millions of patients worldwide. Current treatment AUTHOR CONTRIBUTIONS Sameh Saber implemented conceptualization of this research idea, methodology development, experiments, preparation of cubosomes, writing original draft, data collection, data analysis, editing, interpretation, and final revision;