YDJC restrains Th1 cell differentiation by blocking SREBP2-mediated cholesterol biosynthesis to alleviate mucosal...

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.