{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:31:56Z","timestamp":1788809516191,"version":"build-2803163510"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Activating transcription factor 4 (ATF4) functions as the central transcriptional arbiter of the integrated stress response (ISR) in neurons. Its translation is gated by diverse upstream kinases via the eIF2\u03b1 pathway, while its functional output is critically shaped by context-dependent interactions with specific protein partners (e.g., C\/EBP\u03b2 or CHOP). We conceptualize ATF4 as a spatiotemporal rheostat whose regulatory mandate is stage-specific: it acts as a physiological switch during neocortical development and maintains synaptic and mitochondrial integrity in the adult brain. However, this precise regulation fails in neurological disorders, including Alzheimer\u2019s disease, Parkinson\u2019s disease, cerebral ischemia, and epilepsy. Chronic, maladaptive ATF4 signaling\u2014often driven by pathological heterodimerization\u2014catalyzes neuroinflammation, ferroptosis, and circuit failure. Crucially, contemporary challenges in clinical translation highlight a \u201ctherapeutic paradox,\u201d where broad or untimely pathway inhibition may inadvertently dismantle essential neuroprotective shields. We therefore advocate for a paradigm shift toward \u201ckinetic recalibration\u201d\u2014the development of precision interventions designed to restore the proteostatic and information-processing homeostasis of the stressed nervous system.<\/jats:p>","DOI":"10.3389\/fnmol.2026.1816333","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:47:29Z","timestamp":1781156849000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention"],"prefix":"10.3389","volume":"19","author":[{"given":"Hua","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenggang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuxue","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"104725","DOI":"10.1016\/j.nbd.2019.104725","article-title":"The drug adaptaquin blocks ATF4\/CHOP-dependent pro-death Trib3 induction and protects in cellular and mouse models of Parkinson\u2019s disease.","volume":"136","author":"Aim\u00e9","year":"2020","journal-title":"Neurobiol. 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