2. Academic Validation
  3. YDJC restrains Th1 cell differentiation by blocking SREBP2-mediated cholesterol biosynthesis to alleviate mucosal inflammation in inflammatory bowel disease

YDJC restrains Th1 cell differentiation by blocking SREBP2-mediated cholesterol biosynthesis to alleviate mucosal inflammation in inflammatory bowel disease

  • Cell Mol Immunol. 2025 Oct 29. doi: 10.1038/s41423-025-01361-z.
Ai Li # 1,  Dengfeng Kang # 1,  Zhongsheng Feng # 1,  Haifeng Lian # 2,  Xiang Gao 1,  Xiaohan Wu 1,  Han Gao 1,  Xiaoyu Li 1,  Fushun Kou 1,  Jian Lin 1,  Jinghan Hua 1,  Long Ju 1,  Zixuan Xu 1,  Pingchang Yang 3,  Xue Li 4,  Zhanju Liu 5
Affiliations

Affiliations

  • 1 Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong province, China.
  • 3 Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
  • 4 Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, China. xueli157@zju.edu.cn.
  • 5 Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. zhanjuliu@tongji.edu.cn.
  • # Contributed equally.
PMID: 41162693 DOI: 10.1038/s41423-025-01361-z
Abstract

YdjC chitooligosaccharide deacetylase homolog (YDJC) has been identified as a susceptibility gene for inflammatory bowel disease (IBD), yet its role in the pathogenesis of IBD, particularly in regulating immune responses in the gut mucosa, remains elusive. In this study, we demonstrated that YDJC expression is downregulated in inflamed mucosa, particularly in the CD4+ T cells of IBD patients, and that Ydjc deficiency promotes CD4+ T-cell proliferation and Th1 cell differentiation, thereby exacerbating acute and chronic colitis in mice. Integrative transcriptomic, proteomic, and metabolomic analyses revealed that Ydjc-/-CD4+ T cells exhibit upregulated SREBP2-mediated Cholesterol biosynthesis. Consistently, treatment with key enzyme inhibitors targeting Cholesterol biosynthesis, including simvastatin, fatostatin, and AAV-sh-Srebf2, markedly suppressed CD4+ T-cell proliferation and Th1 cell differentiation, thereby alleviating colitis in Ydjc-/- mice. Mechanistically, YDJC directly deacetylates SREBP2, which further suppresses downstream target gene expression (e.g., Hmgcr, Hmgcs1, and CYP51). Therefore, our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation, suggesting that targeting YDJC and SREBP2-mediated Cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.

Keywords

CD4+ T cells; Cholesterol biosynthesis; Intestinal inflammation; SREBP2; YDJC.

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