Miconazole alleviates colitis by suppressing colonic senescence, NF-κB Signaling and gut microbiota modulation.

Ulcerative colitis (UC) is a chronic relapsing non-transmural inflammatory bowel disease characterized by bloody diarrhea, closely associated with intestinal epithelial cell senescence and chronic inflammation. This study reveals novel mechanisms of the imidazole antifungal drug Miconazole (MCZ) in UC treatment. Through compound library screening, we found that MCZ effectively inhibits dextran sulfate sodium (DSS)-induced senescence in colonic epithelial NCM460 cells. Although clinically used for over 40 years, its anti-senescence and anti-inflammatory mechanisms remain unclear. Experiments confirmed that MCZ significantly reduces DSS-induced SA-β-Gal-positive cell proportion and P16/P21 expression. In animal models, MCZ ameliorated DSS-induced weight loss, bloody stools, and colonic tissue damage. Mechanistic studies demonstrated that MCZ specifically modulates microbiota composition (enriching beneficial bacteria Adlercreutzia, Lactobacillus, Ligilactobacillus, and Limosilactobacillus, while suppressing the relative abundance of Mycoplasma, Oscillibacter, and Streptococcus), and inhibits inflammatory progression by blocking the phosphorylation cascade of the NF-κB signaling pathway. These findings not only reveal MCZ's novel anti-senescence and anti-inflammatory functions but also provide potential new strategies for UC treatment.