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@ARTICLE{Schinke:285355,
      author       = {Schinke, Christian and Maierhof, Smilla K and Hew, Lois and
                      Fernandez Vallone, Valeria and Frahm, Silke and Telugu,
                      Narasimha Swamy and Diecke, Sebastian and Ivanov, Andranik
                      and Kovács, Richard and Beule, Dieter and Kirchner,
                      Marieluise and Mertins, Philipp and Brüning, Ulrike and
                      Kirwan, Jennifer A and Stachelscheid, Harald and Endres,
                      Matthias and Huehnchen, Petra and Boehmerle, Wolfgang},
      title        = {{T}ime‑resolved multi-omic analysis of paclitaxel
                      exposure in human i{PSC}‑derived sensory neurons unveils
                      mechanisms of chemotherapy‑induced peripheral neuropathy.},
      journal      = {Cell death $\&$ disease},
      volume       = {17},
      number       = {1},
      issn         = {2041-4889},
      address      = {London [u.a.]},
      publisher    = {Nature Publishing Group},
      reportid     = {DZNE-2026-00221},
      pages        = {211},
      year         = {2026},
      abstract     = {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.},
      keywords     = {Humans / Paclitaxel: adverse effects / Paclitaxel:
                      pharmacology / Peripheral Nervous System Diseases:
                      chemically induced / Peripheral Nervous System Diseases:
                      pathology / Peripheral Nervous System Diseases: metabolism /
                      Peripheral Nervous System Diseases: genetics / Sensory
                      Receptor Cells: drug effects / Sensory Receptor Cells:
                      metabolism / Sensory Receptor Cells: pathology / Induced
                      Pluripotent Stem Cells: metabolism / Induced Pluripotent
                      Stem Cells: drug effects / Cell Survival: drug effects /
                      Multiomics / Paclitaxel (NLM Chemicals)},
      cin          = {AG Endres},
      ddc          = {570},
      cid          = {I:(DE-2719)1811005},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41667428},
      pmc          = {pmc:PMC12921266},
      doi          = {10.1038/s41419-026-08445-2},
      url          = {https://pub.dzne.de/record/285355},
}