Targeting 14-3-3z by a small-molecule compound AI-34 maintains epithelial barrier integrity and alleviates colitis in mice via stabilizing (3-catenin

Aberrant intestinal epithelial barrier function is the primary pathology of Ulcerative colitis (UC), making it a desirable drug target. In this study, our small-molecule compound AI-34 exerted a significant protective effect in an LPS-induced epithelial barrier injury model. In vitro, AI-34 treatment significantly decreased cell permeability, increased transmembrane resistance, and maintained the junctional protein (ZO-1 and E-cadherin) levels in monolayer cells. Using the LiP-small molecule mapping approach (LiPSMap), we demonstrated that AI-34 binds to 14-3-3z. AI-34 promoted the interaction between 14-3-3z and (3-catenin, decreasing the ubiquitination of (3-catenin and thus maintaining intestinal epithelial barrier function. Finally, AI-34 triggered the stabilization of (3-catenin mediated by 14-3-3z, provoking a significant improvement in the DSS-induced colitis model. Our findings suggest that AI-34 may be a promising candidate for UC treatment.& COPY; 2023 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).