{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T12:41:54Z","timestamp":1773837714671,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R00EY031339-05"],"award-info":[{"award-number":["R00EY031339-05"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cells respond to metabolic and environmental challenges through the integrated stress response (ISR), a cellular process that maintains homeostasis under diverse stressors. ATF4 is a key player in this ISR, as it is activated via the PERK\u2013eIF2\u03b1\u2013ATF4 pathway. ATF4 induction can elicit adaptive responses, including the regulation of genes involved in metabolism and autophagy, to maintain homeostasis. However, ATF4 activation can also induce apoptosis, leading to a wide spectrum of diseases, including metabolic, neurologic, and ocular pathologies. This duality reflects the highly context-dependent nature of ATF4 signaling. This review aims to synthesize the role of ATF4 in metabolic dysfunction, neurodegenerative diseases, and ocular pathology; the mechanisms underlying its protective versus pathologic effects; and future directions to refine ATF4\u2019s potential as a clinical therapeutic target across different diseases.<\/jats:p>","DOI":"10.3390\/cells15060538","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:10:04Z","timestamp":1773825004000},"page":"538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of Activating Transcription Factor 4 in Metabolic, Neurologic, and Ocular Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5178-6404","authenticated-orcid":false,"given":"Minwoo","family":"Kwon","sequence":"first","affiliation":[{"name":"Eye and Vision Research Institute, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6238-1385","authenticated-orcid":false,"given":"Anisha","family":"Kasi","sequence":"additional","affiliation":[{"name":"Eye and Vision Research Institute, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7933-7432","authenticated-orcid":false,"given":"Stefan Y.","family":"Kim","sequence":"additional","affiliation":[{"name":"Eye and Vision Research Institute, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arya","family":"Bairat","sequence":"additional","affiliation":[{"name":"Eye and Vision Research Institute, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aidan","family":"Kumar","sequence":"additional","affiliation":[{"name":"Eye and Vision Research Institute, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varun","family":"Kumar","sequence":"additional","affiliation":[{"name":"Eye and Vision Research Institute, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"},{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Koryga","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1089\/ars.2007.1764","article-title":"Translational control and the unfolded protein response","volume":"9","author":"Wek","year":"2007","journal-title":"Antioxid. 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