Sparfloxacin ameliorates DSS-induced ulcerative colitis by suppressing cellular senescence, JAK/NF-κB signaling pathway and modulation of the gut microbiota-metabolite axis

文献类型： 外文期刊

第一作者： Song, Shujia

作者： Song, Shujia;Li, Fuxing;Zhao, Bingxiang;Xu, Yaxing;Liu, Zhenlin;Liu, Jiayu;Hou, Qinran;Chen, Jiale;Chen, Mengting;Liu, Zhengze;Zhou, Min;Wang, Xiaobo;Wu, Xiaojian

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关键词： Ulcerative colitis; Intestinal senescence; Inflammation; JAK/NF-kappa B

期刊名称：BIOCHEMICAL PHARMACOLOGY （ 影响因子：5.6； 五年影响因子：5.7 ）

ISSN： 0006-2952

年卷期： 2025 年 241 卷

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收录情况： SCI

摘要： The progression of ulcerative colitis (UC) involves immune dysregulation, intestinal barrier dysfunction, and microbial dysbiosis while existing targeted therapies present challenges, including adverse effects and economic burdens. UC is characterized by persistent intestinal inflammation, manifesting as abdominal pain, hematochezia, and malnutrition. Prolonged uncontrolled inflammation may lead to colorectal cancer or severe complications, significantly impairing quality of life. Recent studies have revealed a significant correlation between pathological accumulation of senescent cells and UC pathogenesis, suggesting anti-senescence therapeutics as potential interventions. In this study, we identified sparfloxacin (SPA), a fluoroquinolone antibiotic, through high-throughput screening as an effective senolytic agent that markedly alleviates DSS-induced murine colitis. Mechanistically, combining cellular and animal experiments with transcriptomic, untargeted metabolomic, and metagenomic analyses, we demonstrated sparfloxacin's tripartite therapeutic effects: (1) Senescence inhibition via downregulation of p16/p21 expression; (2) Effective suppression of aberrant JAK/NF-kappa B signaling activation with a concomitant reduction in pro-inflammatory cytokines (TNF-alpha, IL-6); (3) Gut microbiota remodeling characterized by increased probiotic abundance and elevated levels of beneficial metabolites. This study for the first time elucidates the molecular mechanism whereby SPA ameliorates UC through coordinated multi-target actions involving senescence inhibition, anti-inflammatory effects, and microbiome restoration. Our findings not only expand the clinical applications of fluoroquinolones but also provide a theoretical foundation for developing integrated UC treatment strategies targeting cellular senescence.

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