• Cailin Wang, Yanmin Chang, Jiahui Zhu, Rong Ma, and Gang Li.
• Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
• Neuroscience. 2022 Nov 21; 505: 157170157-170.

AbstractThe prevalence of neurodegenerative disease has increased as an outcome of the aging population, and effective clinical treatments for such diseases are lacking. Endoplasmic reticulum dysfunction has been identified as a causative factor in various neurological disorders. The inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) signaling pathway is the most conserved branch of the unfolded protein response, functioning in both physiological and pathological processes. The modulation of IRE1α-XBP1 signaling via genetic manipulation or drug administration has opposite effects in multiple disease models of neurodegeneration, indicating the complex and heterogeneous role of IRE1α-XBP1 signaling among neurodegenerative diseases and even at different stages within the same disease. Herein, we focus on the multifaceted nature of IRE1α-XBP1 signaling and provide a detailed overview of the latest findings regarding its biological relevance in brain physiology and neurodegenerative disease pathobiology. Moreover, the possible pharmacological targets in the IRE1α-XBP1 axis are discussed.Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

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