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000285355 1001_ $$00000-0003-0199-9672$$aSchinke, Christian$$b0
000285355 245__ $$aTime‑resolved multi-omic analysis of paclitaxel exposure in human iPSC‑derived sensory neurons unveils mechanisms of chemotherapy‑induced peripheral neuropathy.
000285355 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2026
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000285355 520__ $$aThe microtubule-stabilizing drug paclitaxel remains the standard of care for various solid malignancies but frequently leads to chemotherapy-induced peripheral neuropathy (CIPN). 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 JUN as an early immediate gene, followed by the overexpression of genes of the neuronal stress response (e.g., ARID5A, WEE1, DUSP16, GADD45A), neuronal injury and apoptotic pathways (e.g., ATF3, HRK, BBC3 [PUMA], BCL2L11 [BIM], CASP3), neuroinflammation and nociception (CALCB, MMP10, IL31RA, CYSLTR2, C3AR1, TNFRSF12A) and neuronal transduction (e.g., CAMK2A, STOML3, PIRT), while key enzymes of lipid biosynthesis were markedly downregulated (e.g., LSS, HMGCS1, HMGCR, DHCR24). Deep proteome analyses following 48 h of exposure to 100 nM 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.
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000285355 650_7 $$0P88XT4IS4D$$2NLM Chemicals$$aPaclitaxel
000285355 650_2 $$2MeSH$$aHumans
000285355 650_2 $$2MeSH$$aPaclitaxel: adverse effects
000285355 650_2 $$2MeSH$$aPaclitaxel: pharmacology
000285355 650_2 $$2MeSH$$aPeripheral Nervous System Diseases: chemically induced
000285355 650_2 $$2MeSH$$aPeripheral Nervous System Diseases: pathology
000285355 650_2 $$2MeSH$$aPeripheral Nervous System Diseases: metabolism
000285355 650_2 $$2MeSH$$aPeripheral Nervous System Diseases: genetics
000285355 650_2 $$2MeSH$$aSensory Receptor Cells: drug effects
000285355 650_2 $$2MeSH$$aSensory Receptor Cells: metabolism
000285355 650_2 $$2MeSH$$aSensory Receptor Cells: pathology
000285355 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000285355 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: drug effects
000285355 650_2 $$2MeSH$$aCell Survival: drug effects
000285355 650_2 $$2MeSH$$aMultiomics
000285355 7001_ $$aMaierhof, Smilla K$$b1
000285355 7001_ $$00000-0002-0183-8177$$aHew, Lois$$b2
000285355 7001_ $$aFernandez Vallone, Valeria$$b3
000285355 7001_ $$00000-0001-5645-2557$$aFrahm, Silke$$b4
000285355 7001_ $$aTelugu, Narasimha Swamy$$b5
000285355 7001_ $$aDiecke, Sebastian$$b6
000285355 7001_ $$aIvanov, Andranik$$b7
000285355 7001_ $$aKovács, Richard$$b8
000285355 7001_ $$aBeule, Dieter$$b9
000285355 7001_ $$00000-0002-7049-534X$$aKirchner, Marieluise$$b10
000285355 7001_ $$00000-0002-2245-528X$$aMertins, Philipp$$b11
000285355 7001_ $$aBrüning, Ulrike$$b12
000285355 7001_ $$00000-0002-5423-1651$$aKirwan, Jennifer A$$b13
000285355 7001_ $$00000-0002-9283-4605$$aStachelscheid, Harald$$b14
000285355 7001_ $$0P:(DE-2719)2811033$$aEndres, Matthias$$b15
000285355 7001_ $$00000-0002-6825-7270$$aHuehnchen, Petra$$b16
000285355 7001_ $$00000-0001-7195-3894$$aBoehmerle, Wolfgang$$b17
000285355 773__ $$0PERI:(DE-600)2541626-1$$a10.1038/s41419-026-08445-2$$gVol. 17, no. 1, p. 211$$n1$$p211$$tCell death & disease$$v17$$x2041-4889$$y2026
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