EPHX2 Orchestrates Intestinal Epithelial Barrier Repair in Ulcerative Colitis: An Integrated Multi‐Omics and Experimental Study

ABSTRACT

Genetic determinants are central to ulcerative colitis (UC) pathogenesis, yet their identification via single‐cell transcriptomics and clinical translation remains incomplete. We integrated GWAS‐eQTL data with UC‐related differentially expressed genes (DEGs) to screen causal genes, mapped them in single‐cell datasets, and prioritized Epoxide Hydrolase 2 (EPHX2) due to the key role of intestinal epithelial cells (IECs) in UC. Colitis mouse and in vitro inflammation models were used to validate EPHX2 expression. Gene Set Enrichment Analysis (GSEA) and functional assays explored its role in mechanisms such as wound healing. EPHX2, a causal gene expressed across epithelial subpopulations, was significantly downregulated in colitis models and cytokine‐stimulated NCM460 cells. GSEA suggested its involvement in mucosal healing, and functional studies confirmed that EPHX2 deficiency impairs mucosal repair capacity. We propose that EPHX2 deficiency may compromise IEC‐mediated mucosal healing in UC. This work advances the understanding of genetic determinants in UC and highlights a potential therapeutic target for disease management.