Bacterial infection or abnormal colonization in the gastrointestinal system is associated with subsets of inflammatory bowel disease and colorectal cancer. Here we demonstrated essential roles of ubiquitin-specific protease 25 (USP25) in experimental colitis, bacterial infections and colon cancer. Knockout or pharmacologic inhibition of USP25 potentiated immune responses after induction of experimental colitis or bacterial infections that promoted clearance of infected bacteria and resolution of inflammation and attenuated Wnt and SOCS3–pSTAT3 signaling, which inhibited colonic tumorigenesis. USP25 levels were positively or negatively correlated with Fusobacterium nucleatum colonization and β-catenin levels or SOCS3 levels in human colorectal tumor biopsies, respectively, and predicted poor prognosis of patients with cancers in the gastrointestinal system. Our findings suggest USP25 as a promoter and druggable target for gastrointestinal infections and cancers.

胃肠道系统中的细菌感染或异常定植与炎症性肠病和结直肠癌的亚类有关。在这里，我们展示了泛素特异性蛋白酶 25 (USP25) 在实验性结肠炎、细菌感染和结肠癌中的重要作用。在诱导实验性结肠炎或细菌感染后，敲除或药理学抑制 USP25 可增强免疫反应，从而促进感染细菌的清除和炎症的消退，并减弱 Wnt 和 SOCS3-pSTAT3 信号传导，从而抑制结肠肿瘤的发生。USP25水平与具核梭杆菌呈正相关或负相关人类结直肠肿瘤活检中的定植和β-连环蛋白水平或SOCS3水平分别预测胃肠系统癌症患者的不良预后。我们的研究结果表明，USP25 是胃肠道感染和癌症的促进剂和药物靶点。