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Biosci. (Landmark Ed)"],"abstract":"<jats:p>The endoplasmic reticulum (ER) stress response is a critical cellular program that maintains proteostasis and membrane homeostasis through the activation of the ER stress sensor proteins inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and old astrocyte specifically induced substance (OASIS) family proteins. These sensors, canonically understood as transducers of the unfolded protein response (UPR), respond to the accumulation of misfolded proteins in the ER lumen as a result of ER luminal Ca2+ depletion, defective disulfide bond formation, dysregulated glycosylation, or inhibition of ER-associated degradation. However, recent conceptual advances have reshaped understanding of these classical mechanisms, by revealing multiple non-canonical pathways that operate independently of luminal proteotoxicity. Emerging evidence highlights the roles of ER stress sensors in integrating diverse stimuli, including the integrated stress response, lipid bilayer stress, mitochondria-ER contact, and the DNA damage response. Herein, we discuss how these ER stress sensors function as multidimensional signaling hubs for proteotoxic, metabolic, and genomic stresses, and consequently modulate pathophysiological cellular outcomes. Finally, we examine current knowledge regarding both canonical and non-canonical modes of ER stress sensor activation, and we discuss how these mechanisms expand the functional scope of ER stress signaling in physiological regulation and diseases.<\/jats:p>","DOI":"10.31083\/fbl50701","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:50:51Z","timestamp":1783421451000},"source":"Crossref","is-referenced-by-count":0,"title":["Broad Roles of Endoplasmic Reticulum Stress Sensors Activated by Diverse Pathophysiological Stimuli"],"prefix":"10.31083","volume":"31","author":[{"given":"Kenshiro","family":"Fujise","sequence":"first","affiliation":[{"name":"Department of Frontier Science and Interdisciplinary Research, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 920-8640 Kanazawa, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himari","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Frontier Science and Interdisciplinary Research, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 920-8640 Kanazawa, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Frontier Science and Interdisciplinary Research, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 920-8640 Kanazawa, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunao","family":"Kamikawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University, 734-8553 Hiroshima, Hiroshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Imaizumi","sequence":"additional","affiliation":[{"name":"The Osaka Medical Research Foundation for Intractable Diseases, 558-0041 Osaka, Osaka, Japan"},{"name":"Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, 565-0871 Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2425-3371","authenticated-orcid":true,"given":"Atsushi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Frontier Science and Interdisciplinary Research, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 920-8640 Kanazawa, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Jang W, Haucke V. 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