{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:55:20Z","timestamp":1792050920226,"version":"4.4.0"},"reference-count":185,"publisher":"The Company of Biologists","issue":"19","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Glioblastoma is the most aggressive and lethal malignancy of the central nervous system and exhibits a complex interplay with endoplasmic reticulum (ER) stress (ERS). The multifunctional ER is the primary site of the unfolded protein response (UPR), which is activated under conditions of ERS to enhance protein-folding capacity and promote cell survival. However, persistent ERS can trigger apoptosis. Despite extensive research over the past decades, the mechanistic insights into the impact of ERS and the UPR on glioblastoma pathogenesis and progression remain unclear. The UPR operates through three canonical signaling pathways: inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK, also known as EIF2AK3) and activating transcription factor 6 (ATF6). These pathways regulate glioblastoma development through both independent and synergistic mechanisms. In this Review, we discuss the current state of research on the role of the UPR in glioblastoma and delineate the distinct mechanisms of each signaling pathway. Furthermore, we evaluate the challenges associated with UPR-targeting therapeutic agents and propose possible treatment strategies to leverage the regulatory mechanisms of the different UPR pathways to overcome these limitations.<\/jats:p>","DOI":"10.1242\/jcs.264879","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:39:04Z","timestamp":1792049944000},"source":"Crossref","is-referenced-by-count":0,"title":["Understanding the unfolded protein response in glioblastoma"],"prefix":"10.1242","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0303-692X","authenticated-orcid":false,"given":"Kaixiang","family":"Ni","sequence":"first","affiliation":[{"name":"Ottawa Hospital Research Institute 1 , Regenerative Medicine Program, Ottawa, ON K1H 8L6 ,","place":["Canada"]},{"name":"University of Ottawa 2 Department of Cellular and Molecular Medicine, Faculty of Medicine , , Ottawa, ON K1H 8M5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9357-668X","authenticated-orcid":false,"given":"Chenchen","family":"Shi","sequence":"additional","affiliation":[{"name":"Yixing Guanlin Town Health Center 3 , Yixing, 214251, Jiangsu Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7246-7349","authenticated-orcid":false,"given":"Jiantong","family":"Jiao","sequence":"additional","affiliation":[{"name":"Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center of Nanjing Medical University 4 Department of Neurosurgery , , Wuxi, 214023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7400-0730","authenticated-orcid":false,"given":"Jun","family":"Sun","sequence":"additional","affiliation":[{"name":"Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center of Nanjing Medical University 4 Department of Neurosurgery , , Wuxi, 214023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9158-300X","authenticated-orcid":false,"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanfang Hospital, Southern Medical University 5 Department of Neurosurgery , , Guangzhou, 510515, Guangdong Province ,","place":["People's Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2138-4330","authenticated-orcid":false,"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"Ottawa Hospital Research Institute 1 , Regenerative Medicine Program, Ottawa, ON K1H 8L6 ,","place":["Canada"]},{"name":"University of Ottawa 2 Department of Cellular and Molecular Medicine, Faculty of Medicine , , Ottawa, ON K1H 8M5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"2026101503385750700_JCS264879C1","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.lungcan.2013.08.008","article-title":"Interaction between non-small-cell lung cancer cells and fibroblasts via enhancement of TGF-beta signaling by IL-6","volume":"82","author":"Abulaiti","year":"2013","journal-title":"Lung Cancer"},{"key":"2026101503385750700_JCS264879C2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1247\/csf.07044","article-title":"ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum","volume":"33","author":"Adachi","year":"2008","journal-title":"Cell Struct. 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