Glioblastoma multiforme (GBM) remains the most aggressive primary brain tumor with poor prognosis and limited response to current therapies. Recent studies suggest that the unfolded protein response (UPR), particularly the inositol-requiring enzyme 1 (IRE1) signaling arm, plays a pivotal role in GBM pathophysiology by mediating cellular adaptation to endoplasmic reticulum stress. This systematic review evaluates the role of IRE1 in GBM cell lines (U87, U251) and investigates whether its activation or inhibition affects migration, proliferation, apoptosis, and cell death. A comprehensive search was conducted on PubMed/ Medline, Scopus, Web of Science, and Embase using various keywords up to October 14, 2025, following the PRISMA guidelines. The search aimed to identify original English-language studies that specifically examined and analyzed the IRE1 arm of the UPR pathway in glioblastoma cells. Out of 466 records, 26 studies met the inclusion criteria. Twenty studies explored IRE1 activation, while six investigated its inhibition. IRE1 activation yielded dual effects-promoting apoptosis via JNK or XBP1 pathways in some contexts, while supporting tumor survival and angiogenesis through XBP1-mediated transcription and RIDD suppression in others. Dual role of IRE1 could sensitize GBM cells to chemotherapy agents, reduced migration and proliferation, and induced apoptosis. IRE1 acts as a context-dependent regulator in GBM, showing both pro-survival and pro-death roles. Most studies report that IRE1 activation promotes glioblastoma cell death, while fewer address its inhibition. Thus, both activation and inhibition may offer therapeutic potential depending on cellular context and downstream signaling.
Ghavamizadeh et al. (Thu,) studied this question.