Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of a growing list of human diseases, including diabetes, obesity, atherosclerosis, and neurodegenerative diseases. Chronic ER stress leads to cell dysfunction and death through the hyperactivation of the unfolded protein response (UPR), and hence has been proposed as a therapeutic target for the treatment of these diseases. However, no drugs targeting ER stress/UPR-induced cell dysfunction and death have yet been identified. Using high throughput screen technology, we have identified a natural product, a furanochromone derivative, as a molecule of cytoprotection against ER stress. Our preliminary studies revealed that (a) in cell-based assays, the furanochromone derivative protects β cells against ER stress-, glucotoxicity-, and lipotoxicity-induced dysfunction and death, (b) the furanochromone ameliorates hyperglycemia and protects the function and survival of β cells in streptozotocin-induced diabetic animals, and (c) the furanochromone also protects other cell types against ER stress. These studies revealed for the first time that this natural product exhibits cytoprotection against ER stress. Our pilot studies further indicate that the furanochromone derivative selectively inhibits the ER stress-induced activation of one of three unfolded protein response pathways, IRE1α pathway, with no effect on the other two pathways: PERK and ATF6. These findings led to our central hypothesis that this compound inhibits ER stress-induced IRE1α hyperactivation to confer cytoprotection. In this grant, we propose three aims to test this hypothesis. In aim 1, we will determine the mechanism of action of this compound on IRE1α inhibition. We will use biochemical assays to determine the effects of the furanochromone derivative on IRE1a kinase and RNase activities and its phosphorylation and dimeric/oligomeric statuses. In aim 2, we will determine whether the compound confers cytoprotective activity by inhibiting IRE1α. These studies will establish its inhibition on IRE1α activation as the molecular mechanism of the compound’s cytoprotection. Finally, we will determine therapeutic potential of the compound in well-established ER stress-related animal models: two diabetes models of progressive β cell loss (Akita mice and db/db mice). Together, this work will reveal not only a novel cytoprotective activity of the natural product against ER stress but also elucidate its inhibition of IRE1α activity as the molecular mechanism of action underlying its cytoprotection, thus establishing the foundation for the clinical development of the furanochromone derivatives as novel cytoprotective drugs for ER stress-related diseases.