Retapamulin alleviates DSS-induced ulcerative colitis via direct AMPK activation and modulation of the gut microbiota-metabolite axis.

Ulcerative colitis (UC), a principal subtype of inflammatory bowel disease, is characterized by chronic inflammation of the intestinal mucosa. In previous studies, intestinal senescence has been shown to exacerbate UC symptoms by promoting inflammation, indicating a potential mechanistic connection between intestinal senescence and UC. In this study, we established DSS-induced senescence models in colonic epithelial cells (NCM460) and UC mouse models. Through an anti-senescence compound screening, we identified the topical antibiotic Retapamulin (RET) as a novel agent that concurrently mitigates colonic senescence and ameliorates UC symptoms. Network pharmacology analysis revealed that RET exerts its anti-senescence and therapeutic effects by activating the AMPK signaling pathway, restructuring the gut microbiota, increasing the abundance of beneficial bacteria, and enhancing the biosynthesis of their metabolites-collectively defining a unique "drug-microbiota-host" synergistic mechanism. In vitro and in vivo experiments confirmed that this newly identified regulatory axis effectively improves the senescent phenotype in both intestinal epithelial cells and colonic tissues, and alleviates symptoms in DSS-induced UC. This study presents a novel anti-senescence intervention strategy for treating UC and demonstrates the regulatory role of microbiota-host signaling pathway interactions in intestinal inflammation.