TY  - JOUR
AU  - Schinke, Christian
AU  - Maierhof, Smilla K
AU  - Hew, Lois
AU  - Fernandez Vallone, Valeria
AU  - Frahm, Silke
AU  - Telugu, Narasimha Swamy
AU  - Diecke, Sebastian
AU  - Ivanov, Andranik
AU  - Kovács, Richard
AU  - Beule, Dieter
AU  - Kirchner, Marieluise
AU  - Mertins, Philipp
AU  - Brüning, Ulrike
AU  - Kirwan, Jennifer A
AU  - Stachelscheid, Harald
AU  - Endres, Matthias
AU  - Huehnchen, Petra
AU  - Boehmerle, Wolfgang
TI  - Time‑resolved multi-omic analysis of paclitaxel exposure in human iPSC‑derived sensory neurons unveils mechanisms of chemotherapy‑induced peripheral neuropathy.
JO  - Cell death & disease
VL  - 17
IS  - 1
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2026-00221
SP  - 211
PY  - 2026
AB  - The 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.
KW  - Humans
KW  - Paclitaxel: adverse effects
KW  - Paclitaxel: pharmacology
KW  - Peripheral Nervous System Diseases: chemically induced
KW  - Peripheral Nervous System Diseases: pathology
KW  - Peripheral Nervous System Diseases: metabolism
KW  - Peripheral Nervous System Diseases: genetics
KW  - Sensory Receptor Cells: drug effects
KW  - Sensory Receptor Cells: metabolism
KW  - Sensory Receptor Cells: pathology
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: drug effects
KW  - Cell Survival: drug effects
KW  - Multiomics
KW  - Paclitaxel (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41667428
C2  - pmc:PMC12921266
DO  - DOI:10.1038/s41419-026-08445-2
UR  - https://pub.dzne.de/record/285355
ER  -