Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex etiology, and its pathological process is closely associated with cellular senescence. Based on an anti-senescence drug screening system, this study identified Tucidinostat (TUC) as an agent with anti-senescence properties and investigated its therapeutic potential and mechanisms of action in a DSS-induced ulcerative colitis model. Using an in vitro model of colonic epithelial cells and an in vivo C57BL/6 mouse model, both induced by DSS treatment, we systematically evaluated changes in body weight, colon length, histopathological scores, levels of inflammatory cytokines, and senescence-associated markers. Our results demonstrated that TUC significantly inhibited cellular senescence and effectively alleviated colitis-related symptoms. Transcriptomic analysis and Western blotting further revealed that TUC exerts its effects by modulating the p53 signaling pathway and cell cycle progression. Furthermore, integrated metagenomic and untargeted metabolomic analyses revealed that TUC reshapes the gut microbiota-metabolite axis by promoting the proliferation of beneficial bacteria (e.g., s__Eubacterium plexicaudatum and s__Ligilactobacillus murinus) and increasing the levels of beneficial metabolites, such as alpha-muricholic acid and kynurenic acid. In summary, this study provides the first evidence that Tucidinostat can ameliorate ulcerative colitis by targeting cellular senescence, regulating the p53/cell cycle signaling network, and restoring gut microbiota-metabolite homeostasis, offering a novel potential therapeutic strategy for this disease.
