Discovery of novel 8-hydroxyquinoline derivatives as NLRP3 inflammasome inhibitors with therapeutic potential for inflammatory bowel disease.

The activation of the NLRP3 inflammasome occurs through two distinct phases-priming and activation-and plays a significant role in various diseases including inflammatory conditions, cancer, and autoimmune disorders. Recent studies have highlighted its critical involvement in the development and progression of inflammatory bowel disease (IBD). In this study, we identified a novel 8-hydroxyquinoline derivative, compound 10, as a potent inhibitor of NLRP3 inflammasome activation. Mechanistic studies demonstrated that 10 disrupts key protein-protein interactions, including NEK7-NLRP3, NLRP3-NLRP3, NLRP3-ASC, and ASC-ASC, thereby preventing NLRP3 inflammasome activation. Notably, 10 exhibited significant anti-inflammatory efficacy in a DSS-induced ulcerative colitis model, highlighting its in vivo therapeutic potential.