IRE1α

IRE1α (inositol-requiring enzyme 1 alpha) functions as a transmembrane sensor of endoplasmic reticulum (ER) stress and a key regulator of the unfolded protein response (UPR)^[1][2]. Mechanistically, it possesses dual kinase and endoribonuclease activities, which coordinate adaptive responses to maintain ER proteostasis and control cell fate decisions^[1][3][4]. IRE1α participates in noncanonical processes by modulating mitochondria-associated membranes (MAMs) to regulate calcium flux and bioenergetics independently of its UPR activity^[5][6]. In disease models, IRE1α facilitates cardiomyocyte hypertrophic growth by promoting translation of 5' terminal oligopyrimidine (TOP)-motif mRNAs and sustaining protein synthesis under stress conditions^[2]. It also contributes to cancer progression through degradation of tumor-suppressive mRNAs and activation of pro-survival pathways^[3][4]. Compared with its paralog IRE1β, which is largely restricted to epithelial tissues and displays distinct luminal sensing mechanisms, IRE1α exhibits ubiquitous expression and essential roles in systemic metabolism, immune function, and development^[1][7]. Pharmacologically, selective inhibitors targeting either the RNase or kinase domains of IRE1α can attenuate maladaptive signaling in cancer, neurodegeneration, viral infection, and fibrotic disorders, providing valuable tools for experimental modulation and therapeutic exploration^[4][8][9].