Targeted Deletion of EPHX2 in Intestinal Epithelial Cells Alleviates DSS‐Induced Colitis by Enhancing Goblet Cell Differentiation

ABSTRACT Dysregulation of epoxide hydrolase 2 (‌EPHX2) is associated with the pathogenesis of various diseases. However, the functional role of EPHX2 in ulcerative colitis remains unclear. In this study, we demonstrate that EPHX2 plays a critical role in driving the pathological breakdown of barrier integrity in a colitis model. Pharmacological inhibition of EPHX2 significantly ameliorated Dextran Sulfate Sodium (DSS)‐induced colitis. Notably, conditional knockout of EPHX2 in intestinal epithelial cells (IECs) conferred protection against colitis‐associated mucosal damage. Moreover, EPHX2 deletion in IECs led to increased Muc2 expression and a higher number of goblet cells by promoting goblet cell differentiation, while the expression levels of tight junction proteins (ZO‐1, occludin, and claudin‐1) remained unchanged. These findings identify a previously unrecognized role of EPHX2 in IECs and suggest that targeting EPHX2 may represent a promising therapeutic strategy for ulcerative colitis.