2492-P: The Liver-Enriched AZGP1 Increases Insulin Sensitivity and Glucose Metabolism via EPHA–AKT/GSK3β Signaling

Introduction and Objective: Type 2 diabetes is a metabolic disorder characterized by hyperglycemia associated with obesity-induced peripheral insulin resistance and intrinsic pancreatic islet beta cell dysfunction. Because of the complex pathophysiology and heterogeneity of T2D, the identification of potential therapeutic targets is clinically important. Methods: we analyzed hepatic gene expression profiles from Zucker rats and identified that the key molecular regulators in diabetic pathogenesis by a series interventional studies.The relationship between Azgp1 in the liver and key phenotypes and protein expression related to glucose metabolism and insulin resistance was explored. Proteomic, proximity-dependent biotin identification BioID analysis, and Co-IP assay was performed. siEPHA and ALW-II-41-27(Eph receptor tyrosine kinase inhibitor)are used. Results: Azgp1 is a secreted protein with the most significant expression differences in Zucker rats and Azgp1 expression is modulated by PA, insulin, glucagon and dexamethasone. Azgp1 overexpression ameliorates glucose metabolism and insulin resistance in vitro. Integrative analyses of interactome and Unbiased proteomics revealed a pivotal role of Azgp1 in glucose metabolism and insulin resistance and identified the EPHA as a direct binding partner of Azgp1. Azgp1 directly interacted with EPHA and triggered Akt/GSK3β signaling.Finally, using artificial intelligence-based virtual screening, we discovered an orally bioavailable small-molecule agonist of Azgp1 (named Xan). Therapeutic administration of Xan improved Insulin Sensitivity and glucose metabolism in mice with an optimal safety, tolerability, and pharmacokinetics profile. Conclusion: Our findings provide proof of concept that targeting the Azgp1-EPHA- Akt/GSK3β signaling axis in hepatocytes may offer potential therapeutic avenues to treat T2D. Disclosure W. Hu: None. X. Zhou: None. Funding Chongqing Young and Middle aged Medical High end Talent Project(YXGD202401); Natural Science Foundation of Chongqing, China (CSTB2024NSCQ-MSX1208); Project Of Science and Technology Research Program of Chongqing Education Commission of China (KJQN202402828, KJQN202502801); Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (2026MSXM006)