Ulcerative colitis (UC), a common inflammatory bowel disease (IBD), is characterized by chronic mucosal inflammation. Our previous work established a link between cellular senescence and UC, suggesting that ameliorating cell senescence could be a therapeutic strategy for UC. In this study, we identified dehydrodiisoeugenol (DDIE) as an anti-senescence drug through screening in a DSS-induced colonic epithelial cell senescence model. In a DSS-induced acute mouse model of UC, DDIE effectively suppressed colonic senescence and significantly alleviated UC. Network pharmacology, colonic tissue transcriptomic analysis, and Western blot assays indicated that DDIE's therapeutic effects in UC are associated with the AKT and GSK3B pathways. Subsequent cellular blocking experiments utilizing the AKT activator insulin and the GSK3B inhibitor BIO confirmed that activating AKT or inhibiting GSK3B reversed the anti-senescence and anti-inflammatory effects of DDIE. Our findings demonstrate that DDIE treats UC by inhibiting AKT and activating GSK3B, thereby suppressing cellular senescence and restoring the intestinal barrier. This research offers a novel therapeutic strategy for UC from the perspective of anti-cellular senescence.
