Inhibition of Wnt/β-catenin Signaling Pathway via XAV939 does not mitigate Dextran Sulfate Sodium-Induced Ulcerative Colitis Running Title: XAV939 does not mitigate Ulcerative Colitis

Abstract

The Wnt/β-catenin signaling pathway is known to be hyperactivated during the pathogenesis of ulcerative colitis (UC). This study aimed to explore the therapeutic efficacy of the Wnt/β-catenin signaling inhibitor, XAV939, in mitigating UC symptoms. Utilizing a dextran sulfate sodium (DSS)-induced UC mouse model, we aimed to evaluate the impact of XAV939 on intestinal morphology through hematoxylin and eosin (HE) staining and to measure the expression levels of critical proteins within the Wnt/β-catenin signaling cascade. Contrary to our expectations, XAV939 did not exert a significant influence on the morphological features and inflammatory status of the intestinal epithelium. Nonetheless, XAV939 was found to effectively suppress the Wnt/β-catenin signaling pathway and its downstream target SOX9. This suppression implies a reduction in the differentiation of intestinal stem cells (ISCs) into secretory cell progenitor cells. Additionally, XAV939 was ineffective in reversing the DSS-induced decline of Villin and PPAR-γ, suggesting that it does not facilitate the differentiation of intestinal absorptive cells. Our findings indicate that the Wnt/β-catenin signaling pathway may not be the predominant mechanism in the pathogenesis of DSS-induced UC.