{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T07:25:52Z","timestamp":1786951552947,"version":"build-2736575974"},"reference-count":46,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Irinotecan is a key chemotherapeutic agent, but its neurotoxicity limits its utility. Observed differences in neurotoxicity between conventional and liposomal formulations are poorly characterized mechanistically. This study aimed to systematically compare their neurotoxicity profiles and investigate the underlying mechanisms, testing the hypothesis that the parent drug irinotecan contributes directly to neurotoxicity. We employed a multi\u2010dimensional strategy. Computational toxicology predicted neurotoxicity for irinotecan and its metabolite SN\u201038. Disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) compared real\u2010world neurotoxicity signals. Network pharmacology and molecular docking explored irinotecan's direct molecular targets and pathways. Multi\u2010platform computational prediction confirmed high neurotoxicity risk for both irinotecan and SN\u201038. FAERS analysis revealed a distinct clinical profile: conventional irinotecan (C\u2010Irinotecan) was associated with both central (CNS) and peripheral nervous system (PNS) adverse events, whereas liposomal irinotecan (L\u2010Irinotecan) signals were confined to the periphery. This CNS\u2010specific disparity, combined with pharmacokinetic evidence, implicated the parent drug. Network analysis identified eight core neural targets (e.g., AKT1, EGFR) with high binding affinity to irinotecan. Pathway enrichment highlighted the MAPK\/p38 cascade as a central mechanism. This integrated analysis demonstrates a formulation\u2010dependent neurotoxicity dichotomy for irinotecan. We propose and provide converging evidence for a novel paradigm: prototype irinotecan is a direct mediator of neurotoxicity, and its CNS access dictates central effects. These findings offer critical insights for formulation safety and neuroprotective strategies.<\/jats:p>","DOI":"10.1002\/jbt.71026","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:47:37Z","timestamp":1784641657000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Formulation\u2010Dependent Neurotoxicity of Irinotecan: An Integrated Pharmacovigilance and Mechanistic Study"],"prefix":"10.1002","volume":"40","author":[{"given":"Cheng","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Pharmacy The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital) Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0414-6483","authenticated-orcid":false,"given":"Wei","family":"Ma","sequence":"additional","affiliation":[{"name":"School 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