P0010YDJC restrains Th1 cell differentiation through blocking SREBP2-mediated cholesterol biosynthesis to alleviate mucosal inflammation in inflammatory bowel disease

Abstract Background YdjC chitooligosaccharide deacetylase homolog (YdjC chitooligosaccharide deacetylase homolog (YDJC) has been identified as a susceptibility gene for inflammatory bowel disease (IBD); however, its role in IBD pathogenesis and therapeutic potential against IBD remains unexplored. Therefore, we investigated the role of YDJC in colitis) has been identified as a susceptibility gene for inflammatory bowel disease (IBD), while its role in IBD pathogenesis remains elusive. Methods Human peripheral CD4+ T cells were stimulated, differentiated, and transfected with lentivirus to investigate the function of YDJC. Mouse splenic CD4+ T cells were characterized using various approaches, including transcriptome analysis (RNA sequencing), protein expression profiling (proteomics, flow cytometry), and metabolic assessment (ultra-high-performance liquid chromatography-tandem mass spectrometry) and function assays (activation, proliferation, and differentiation). The in vivo role of YDJC was assessed using both acute and chronic colitis models. Results YDJC expression was decreased in inflamed mucosa, especially in CD4+ T cells of IBD patients. Ydjc deficiency promoted CD4+ T cell proliferation and Th1 differentiation, exacerbating acute and chronic colitis in mice. Integrative transcriptomic, proteomic, and metabolomic analyses revealed upregulated SREBP2-mediated cholesterol biosynthesis in Ydjc-/-CD4+ T cells. Treatment with key enzyme inhibitors in cholesterol biosynthesis, including simvastatin, fatostatin, and AAV-sh-Srebf2, markedly reduced CD4+ T cell proliferation and Th1 differentiation, thereby alleviating colitis in Ydjc-/- mice. Mechanistically, YDJC directly deacetylated SREBP2, influencing its stability and downstream gene expression. Conclusion Our findings elucidate the novel mechanisms by which YDJC modulates intestinal inflammation, suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD. Conflict of interest: Dr. Li, Ai: No conflict of interest