Tucidinostat ameliorates DSS-induced ulcerative colitis by inhibiting cellular senescence, modulating the p53 signaling pathway and cell cycle, and restoring the gut microbiota-metabolite Axis.

Tucidinostat was identified as an anti-senescence agent with therapeutic potential in DSS-induced ulcerative colitis models.

• TUC was identified through an anti-senescence drug screening system.
• Studies were conducted using both in vitro colonic epithelial cell models and in vivo C57BL/6 mouse models induced by DSS treatment.
• TUC significantly inhibited cellular senescence and effectively alleviated colitis-related symptoms.

TUC treatment produced measurable improvements in colitis-associated physical and histopathological parameters.

• Evaluations included changes in body weight, colon length, histopathological scores, levels of inflammatory cytokines, and senescence-associated markers.
• TUC significantly inhibited cellular senescence markers in both in vitro and in vivo models.
• Colitis-related symptoms were effectively alleviated by TUC treatment.

Transcriptomic analysis and Western blotting revealed that TUC modulates the p53 signaling pathway and cell cycle progression.

• Transcriptomic analysis was used to identify pathway-level changes associated with TUC treatment.
• Western blotting confirmed modulation of the p53 signaling pathway.
• TUC was found to regulate the p53/cell cycle signaling network as a mechanism of action.

TUC reshapes the gut microbiota composition by promoting the proliferation of beneficial bacteria.

• Integrated metagenomic analysis was used to assess gut microbiota changes.
• TUC promoted the proliferation of beneficial bacteria including s__Eubacterium plexicaudatum and s__Ligilactobacillus murinus.
• These microbiota changes were characterized as restoring gut microbiota-metabolite homeostasis.

TUC increased the levels of beneficial metabolites as part of its restoration of the gut microbiota-metabolite axis.

• Untargeted metabolomic analysis was used to characterize metabolite changes.
• Beneficial metabolites increased by TUC included alpha-muricholic acid and kynurenic acid.
• These metabolomic findings were integrated with metagenomic data to characterize the gut microbiota-metabolite axis.

The pathological process of ulcerative colitis is closely associated with cellular senescence, providing the mechanistic rationale for targeting senescence with TUC.

• UC is described as a chronic inflammatory bowel disease with a complex etiology.
• The study's anti-senescence drug screening system was used as the basis for identifying TUC as a candidate therapeutic.
• This study provides the first evidence that Tucidinostat can ameliorate ulcerative colitis by targeting cellular senescence.