Oxymatrine ameliorates ulcerative colitis via improving epithelial barrier function through targeting DSG2.

Area of Science:

• Pharmacology
• Gastroenterology
• Molecular Biology

Background:

• Oxymatrine (OMT), derived from Sophora flavescens Ait., shows promise for ulcerative colitis (UC) treatment.
• The precise molecular mechanisms underlying OMT's efficacy in UC remain largely unexplored.

Purpose of the Study:

• To evaluate the therapeutic potential of OMT in a chronic UC mouse model.
• To elucidate the molecular mechanisms by which OMT exerts its therapeutic effects.

Main Methods:

• Utilized a chronic UC mouse model to assess OMT and Sophora flavescens Ait. water extract (WSF).
• Employed proteomic analysis, cell apoptosis models (HCT116, Caco-2), and biophysical techniques (CETSA, DARTS, MST) to identify and validate OMT targets.
• Investigated OMT's impact on intestinal epithelial barrier (IEB) function and its metabolite matrine (MAT).

Main Results:

• OMT and WSF demonstrated significant therapeutic effects, alleviating UC by reducing inflammation and enhancing IEB function.
• Proteomic analysis identified desmoglein-2 (Dsg2) as a key upregulated protein in UC.
• OMT directly binds to Dsg2, stabilizing it and inhibiting caspase-8-mediated cleavage, thereby improving cell adhesion and IEB integrity.

Conclusions:

• Desmoglein-2 (Dsg2) is identified as a direct molecular target of Oxymatrine (OMT) in the context of ulcerative colitis (UC).
• OMT's therapeutic benefits in UC stem from its ability to bind Dsg2, inhibit caspase-8 activity, reduce Dsg2 cleavage, and restore intestinal epithelial barrier function.