<p>YdjC chitooligosaccharide deacetylase homolog (<i>YDJC</i>) 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 <i>YDJC</i> expression is downregulated in inflamed mucosa, particularly in the CD4⁺ T cells of IBD patients, and that <i>Ydjc</i> 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 <i>Ydjc</i>^-/-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 <i>Ydjc</i>^-/- mice. Mechanistically, YDJC directly deacetylates SREBP2, which further suppresses downstream target gene expression (e.g., <i>Hmgcr</i>, <i>Hmgcs1</i>, and <i>Cyp51</i>). 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.</p>