{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:44:17Z","timestamp":1786977857151,"version":"build-2736575974"},"reference-count":68,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Fentanyl, an ultra\u2010potent synthetic opioid, has traditionally been characterized by its acute toxic effects, particularly respiratory depression. However, accumulating research indicates that its neurobiological influence extends far beyond its short pharmacological window, intersecting with several core mechanisms implicated in major neurodegenerative disorders. This review integrates multiscale evidence to propose a unified conceptual framework in which fentanyl may function not only as an acute neurotoxin but also as a putative accelerator of long\u2010term neurodegenerative vulnerability. Drawing from molecular signaling, cellular stress pathways, glial\u2013neuronal cross\u2010talk, neurovascular regulation, synaptic architecture, and large\u2010scale neural networks, we highlight fentanyl's capacity to trigger a convergent cascade encompassing hypoxic\u2013metabolic reprogramming, mitochondrial fragmentation, TLR4\u2013NF\u2010\u03baB\u2013driven inflammation, NLRP3 inflammasome activation, complement\u2010mediated synaptic pruning, astrocytic EAAT2 downregulation, and blood\u2013brain barrier compromise. These alterations propagate through recursive cross\u2010talk loops that progressively diminish neuronal resilience, destabilize oscillatory coherence, and weaken circuit\u2010level adaptability. Importantly, mechanistic overlaps with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis suggest that fentanyl exposure may be mechanistically associated with processes capable of accelerating disease onset, exacerbating progression, or unmasking latent vulnerabilities, particularly in genetically or metabolically predisposed individuals. By reframing fentanyl as a systems\u2010level destabilizer capable of imprinting persistent neurobiological changes, this model underscores the need for comprehensive biomarker development, longitudinal risk assessment, and targeted neuroprotective interventions. The integrative framework presented herein offers a foundation for predicting the long\u2010term neurological consequences of fentanyl exposure and calls for urgent reconsideration of its role in population\u2010level neurodegenerative risk.<\/jats:p>","DOI":"10.1002\/jat.70069","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:28:51Z","timestamp":1769617731000},"page":"1404-1416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Neuroimmune Cross\u2010Talk and Multilevel Cascades in Fentanyl Toxicity: Interplay of Hypoxic Stress, Glial Activation, and Synaptic Dysregulation in Systems\u2010Level Neurodegeneration"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0191-4387","authenticated-orcid":false,"given":"Hamzeh\u00a0J.","family":"Al\u2010Ameer","sequence":"first","affiliation":[{"name":"Faculty of Allied Medical Sciences, Hourani Center for Applied Scientific Research Al\u2010Ahliyya Amman University  Amman Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor\u00a0Mazin","family":"Basheer","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technics, College of Health and Medical Technology Alnoor University  mosul Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malathi","family":"H","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Genetics, School of Sciences JAIN (Deemed to be University)  Bangalore Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aman","family":"Shankhyan","sequence":"additional","affiliation":[{"name":"Centre for Research Impact &amp; Outcome, Chitkara University Institute of Engineering and Technology Chitkara University  Rajpura Punjab India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajashree","family":"Panigrahi","sequence":"additional","affiliation":[{"name":"Department of Microbiology IMS and SUM Hospital, Siksha 'O' Anusandhan  Bhubaneswar Odisha India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vimal","family":"Arora","sequence":"additional","affiliation":[{"name":"University Institute of Pharma Sciences Chandigarh University  Mohali Punjab India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khushnud","family":"Azizjanov","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences Ma'mun University  Khiva Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erkabay","family":"Eshchanov","sequence":"additional","affiliation":[{"name":"Department of Chemistry Urgench State University  Urgench Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6517-8163","authenticated-orcid":false,"given":"Zokir","family":"Ataullaev","sequence":"additional","affiliation":[{"name":"Natural Science Department Urganch State Pedagogical Institute  Urgench Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"e_1_2_13_2_1","volume-title":"Adaptations Following Chronic Opioid Treatment in the Presynaptic and Postsynaptic Compartments of Neuron","author":"Adhikary S.","year":"2021"},{"issue":"10","key":"e_1_2_13_3_1","article-title":"AI in Neurodegenerative Disease Research: Early Detection, Cognitive Decline Prediction, and Brain Imaging Biomarker Identification","volume":"6","author":"Ali H.","year":"2022","journal-title":"International Journal of Engineering Technologies and Management Research"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1140\/epjs\/s11734-025-01591-2"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03505-1"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26020444"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13486"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24357"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology11020300"},{"key":"e_1_2_13_10_1","volume-title":"The Beneficial Effects of an Immunotherapeutic on Preclinical Gulf War Illness Neurological Abnormalities Along the Hippocampal Dorsoventral Axis","author":"Brown K. 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