Because aberrant UPR activation, uncompensated proteostasis, and dysregulated AKT-mTOR signaling are common drivers of major worldwide health threats, including type 2 diabetes and obesity-related syndromes, neurodegenerative diseases, and certain types of cancer such as hepatocellular carcinoma3,61–67, we propose that the AKT-mTOR-dependent IRE1 shutdown mechanism might constitute a novel avenue for therapeutic manipulation. This evidence concerns the gene ERN1 and neurodegenerative disease.