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CIPN is a leading cause for premature treatment termination and a significantly reduced quality of life in long-term cancer survivors. The molecular mechanisms of neuro-axonal degeneration, neuroinflammation, and pain in patients treated with paclitaxel remain incompletely understood, and there are currently no predictive biomarkers or preventive treatments. We used human iPSC-derived sensory neurons exposed to paclitaxel to comprehensively model the pathophysiology of CIPN. Neurotoxicity was assessed over time using viability assays and sequential RNA sequencing, as well as deep proteome and lipidomic analyses. We observed a time and dose-dependent decline of cell viability at clinically relevant paclitaxel doses. Sequential RNA sequencing defined\n                    <jats:italic>JUN<\/jats:italic>\n                    as an early immediate gene, followed by the overexpression of genes of the neuronal stress response (e.g.,\n                    <jats:italic>ARID5A, WEE1<\/jats:italic>\n                    ,\n                    <jats:italic>DUSP16, GADD45A<\/jats:italic>\n                    ), neuronal injury and apoptotic pathways (e.g.,\n                    <jats:italic>ATF3<\/jats:italic>\n                    ,\n                    <jats:italic>HRK, BBC3 [PUMA]<\/jats:italic>\n                    ,\n                    <jats:italic>BCL2L11 [BIM]<\/jats:italic>\n                    ,\n                    <jats:italic>CASP3<\/jats:italic>\n                    ), neuroinflammation and nociception (\n                    <jats:italic>CALCB<\/jats:italic>\n                    ,\n                    <jats:italic>MMP10<\/jats:italic>\n                    ,\n                    <jats:italic>IL31RA<\/jats:italic>\n                    ,\n                    <jats:italic>CYSLTR2<\/jats:italic>\n                    ,\n                    <jats:italic>C3AR1, TNFRSF12A<\/jats:italic>\n                    ) and neuronal transduction (e.g.,\n                    <jats:italic>CAMK2A<\/jats:italic>\n                    ,\n                    <jats:italic>STOML3, PIRT<\/jats:italic>\n                    ), while key enzymes of lipid biosynthesis were markedly downregulated (e.g.,\n                    <jats:italic>LSS, HMGCS1<\/jats:italic>\n                    ,\n                    <jats:italic>HMGCR<\/jats:italic>\n                    ,\n                    <jats:italic>DHCR24<\/jats:italic>\n                    ). Deep proteome analyses following 48\u2009h of exposure to 100\u2009nM paclitaxel revealed a strong correlation of differentially expressed RNA with proteins, and a marked degradation of essential axonal transport proteins such as kinesins, stathmins, and scaffold proteins. Consistent with the downregulation of rate-limiting enzymes of lipid biosynthesis, lipidome analysis confirmed deregulation of neuronal lipid homeostasis. In summary, paclitaxel induces transcriptomic and proteomic signatures of the neuronal stress response, neuroinflammation, nociception, and disturbed metabolism. These may explain, in part, the clinical phenotype of sensory loss, hypersensitivity, and neuropathic pain frequently observed in patients suffering from CIPN, but constitute pharmacologically addressable targets.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08445-2","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T04:36:17Z","timestamp":1770698177000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Time\u2011resolved multi-omic analysis of paclitaxel exposure in human iPSC\u2011derived sensory neurons unveils mechanisms of chemotherapy\u2011induced peripheral neuropathy"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0199-9672","authenticated-orcid":false,"given":"Christian","family":"Schinke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smilla K.","family":"Maierhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0183-8177","authenticated-orcid":false,"given":"Lois","family":"Hew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Fernandez Vallone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5645-2557","authenticated-orcid":false,"given":"Silke","family":"Frahm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narasimha Swamy","family":"Telugu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Diecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andranik","family":"Ivanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Beule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7049-534X","authenticated-orcid":false,"given":"Marieluise","family":"Kirchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-528X","authenticated-orcid":false,"given":"Philipp","family":"Mertins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Br\u00fcning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5423-1651","authenticated-orcid":false,"given":"Jennifer A.","family":"Kirwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9283-4605","authenticated-orcid":false,"given":"Harald","family":"Stachelscheid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-3720","authenticated-orcid":false,"given":"Matthias","family":"Endres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6825-7270","authenticated-orcid":false,"given":"Petra","family":"Huehnchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7195-3894","authenticated-orcid":false,"given":"Wolfgang","family":"Boehmerle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"8445_CR1","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1016\/j.pain.2014.09.020","volume":"155","author":"M Seretny","year":"2014","unstructured":"Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, Macleod MR, et al. 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