Sfrp2-deficient colonic fibroblasts drive mucosal inflammation and epithelial injury in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disorder targeting the colon, which remains clinically challenging due to limited targeted therapies. Although intestinal fibroblasts have emerged as critical regulators of mucosal immunity and tissue repair, their molecular mechanisms in UC pathogenesis are poorly defined. Here, we investigate the functional role of secreted frizzled-related protein 2 (SFRP2, a Wnt signaling modulator) knockdown fibroblasts in immune homeostasis and the severity of UC using Sfrp2^flox/flox; Col1a2-Cre mice (fibroblast-specific knockout). In the dextran sulfate sodium (DSS)-induced colitis model, we found SFRP2 in fibroblasts have negative correlation with the severity of UC. That Sfrp2^Col1a2 CKO mice exhibited exacerbated colitis symptoms and accelerated inflammatory progression, and showed increased ratio of Th17 cells and decreased ratio of Treg cells. These findings revealed that Sfrp2 in fibroblasts plays a crucial role in protecting against inflammatory responses and T-cell immune dysregulation. Therefore, Sfrp2 may serve as a potential therapeutic target for UC treatment.