Inositol-requiring enzyme-1α (IRE-1α) is an endoplasmic reticulum (ER) transmembrane protein that mediates one of the three arms of unfolded protein response (UPR) adaptation to ER stressors. In response to recognition of misfolded proteins in the ER lumen, IRE-1α oligomerizes to activate its cytoplasmic kinase and endoribonuclease domains, which initiate cleavage of the mRNA encoding the transcription factor XBP-1 (x-box binding protein 1), an effector that drives the transcription of cytoprotective genes.1 IRE-1α can either return to an inactive state upon resolution of ER stress or enter a refractive state in which it no longer responds to unresolved ER stress after prolonged activation, limiting the cytoprotective duration of the UPR.2 Increasing evidence suggests that ER stress and IRE-1α are associated with adverse conditions such as diabetes, cancer, muscle degeneration, and neurodegenerative, bipolar, liver, cardiac, and autoimmune diseases.