Unfolded protein response(UPR)is a stress response that is specific to the endoplasmic re-ticulum(ER).UPR is activated upon accumulation of unfolded(or misfolded)proteins in the ER\'s lumen to restore protein folding capacity by increasing the synthesis of chaperones.In addition,UPR also en-hances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accu-mulation of unfolded proteins in the ER.Herein,we describe a cell-based ultra-high throughput screening(uHTS)campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models.Using asialoglycoprotein receptor 1(ASGR)fused with Cypridina luciferase(CLuc)as reporter assay for folding capacity,we have screened a million small molecule library and identified APC655 as a potent activator of protein folding,that appears to act by promoting chaperone expression.Furthermore,APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines.APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient(ob/ob)mouse model.These results demonstrate a successful uHTS campaign that identified a modulator of UPR,which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.