Abstract

Background Isodeoxyelephantopin (IDET) is a sesquiterpene lactone isolated from traditional herb Elephantopus scaber , which is known for its anti-inflammatory activities. While our previous study demonstrated that IDET inhibits NLRP3 expression in an acute peritonitis model, its therapeutic potential in chronic inflammatory diseases such as ulcerative colitis (UC), as well as the underlying mechanisms involving inflammasome signaling, have not yet been fully elucidated. Purpose This research was designed to explain the protective capacity of IDET in UC and to clarify how IDET modulates IL-1β-mediated inflammatory responses through the TXNIP/NLRP3 signaling pathway, by integrating in vitro and in vivo experimental systems. Results IDET significantly reduced dextran sulfate sodium (DSS)-induced colitis in mice, improving disease scores, reducing inflammation, and preserving colon histology. Mechanistically, IDET exerted a multi-tiered suppression of the inflammasome pathway, which suppresses IL-1β-driven inflammation. Firstly, it disrupted the upstream priming signal by downregulating NLRP3 expression through NF-κB signaling pathway. Secondly, it inhibited inflammasome assembly, as evidenced by reduced ASC oligomerization and NLRP3-ASC interaction. Consequently, IDET reduced the cleavage of pro-caspase-1 and pro-IL-1β, resulting in an approximately 4-fold reduction in mature IL-1β secretion. A key finding was that IDET interfered with the activation signal by attenuating the TXNIP-NLRP3 interaction, according to immunoprecipitation and molecular docking results. Conclusions Extending our previous findings on its anti-acute inflammatory activity, this study demonstrates that IDET alleviates experimental ulcerative colitis by targeting multiple stages of NLRP3 inflammasome activation. The results highlight the translational potential of IDET, a natural compound, for treating chronic intestinal inflammation.