Pharmacological inhibition of IRE1α endoribonuclease domain by a novel small molecular inhibitor MKC-3946 could reduce the expression of XBP1s and protect against AD in an Ang II induced mouse model by suppressing XBP1s associated ROS production, phenotypic switch and apoptosis in VSMCs, which potentiates its clinical application in the future. This evidence concerns the gene ERN1 and Alzheimer disease.