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<p>Dysregulated posttranslational modifications drive inflammatory bowel disease (IBD) pathogenesis, yet the specific roles of deubiquitinases in intestinal macrophages remain poorly characterized. Here, we identify ubiquitin-specific peptidase 9X (USP9X) as a critical negative regulator of intestinal inflammation. USP9X expression is reduced in UC patients and inversely correlated with disease severity. Myeloid-specific deletion of USP9X exacerbates colitis in both DSS- and TNBS-induced models, whereas its overexpression ameliorates disease. Mechanistically, USP9X interacts with signal transducer and activator of transcription 1 (STAT1) and removes K27-linked polyubiquitin chains from lysine 544. The loss of USP9X enhances STAT1 nuclear translocation and transcriptional activity, resulting in the upregulation of oncostatin M (OSM) expression and exacerbating inflammation. Mutation of STAT1 at K544 attenuated both basal and USP9X knockdown–induced responses. Notably, neutralizing OSM abrogates the exacerbated colitis phenotype in USP9X-deficient mice. These findings define a USP9X–STAT1–OSM axis that connects ubiquitin editing to transcriptional regulation and represents a potential therapeutic target for IBD.</p><p></p>

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Macrophage USP9X attenuates colitis by restricting oncostatin M production via K27-linked deubiquitination of STAT1

  • 期刊论文

  • 发表日期：

    2026年5月28日

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  • Tao Zhang,
  • Fanyi Meng,
  • Wenjing Zhao,
  • Xiangyu Meng,
  • Jie Xiong,
  • Feifei Chu,
  • Yadi Lan,
  • Jingyi Wang,
  • Qi Chen,
  • Weilong Zhong,
  • Bangmao Wang,
  • Ding Ai,
  • Zhanju Liu,
  • Liu Yao,
  • Hailong Cao

摘要

Dysregulated posttranslational modifications drive inflammatory bowel disease (IBD) pathogenesis, yet the specific roles of deubiquitinases in intestinal macrophages remain poorly characterized. Here, we identify ubiquitin-specific peptidase 9X (USP9X) as a critical negative regulator of intestinal inflammation. USP9X expression is reduced in UC patients and inversely correlated with disease severity. Myeloid-specific deletion of USP9X exacerbates colitis in both DSS- and TNBS-induced models, whereas its overexpression ameliorates disease. Mechanistically, USP9X interacts with signal transducer and activator of transcription 1 (STAT1) and removes K27-linked polyubiquitin chains from lysine 544. The loss of USP9X enhances STAT1 nuclear translocation and transcriptional activity, resulting in the upregulation of oncostatin M (OSM) expression and exacerbating inflammation. Mutation of STAT1 at K544 attenuated both basal and USP9X knockdown–induced responses. Notably, neutralizing OSM abrogates the exacerbated colitis phenotype in USP9X-deficient mice. These findings define a USP9X–STAT1–OSM axis that connects ubiquitin editing to transcriptional regulation and represents a potential therapeutic target for IBD.