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@ARTICLE{Hew:282300,
author = {Hew, Lois and Maierhof, Smilla K and Ivanov, Andranik and
Beule, Dieter and Fernandez Vallone, Valeria and
Stachelscheid, Harald and Frahm, Silke and Telugu, Narasimha
Swamy and Endres, Matthias and Boehmerle, Wolfgang and
Huehnchen, Petra and Schinke, Christian},
title = {c-{J}un inhibition mitigates chemotherapy-induced
neurotoxicity in i{PSC}-derived sensory neurons.},
journal = {Cell death discovery},
volume = {11},
number = {1},
issn = {2058-7716},
address = {London},
publisher = {Nature Publishing Group},
reportid = {DZNE-2025-01270},
pages = {529},
year = {2025},
abstract = {Chemotherapy-induced peripheral neuropathy (CIPN) affects
up to two-thirds of cancer patients undergoing cytotoxic
chemotherapy. Here, we used human iPSC-derived sensory
neurons (iPSC-DSN) to model CIPN in vitro. Administration of
various chemotherapeutic agents (i.e., paclitaxel,
vincristine, bortezomib and cisplatin) at clinically
applicable concentrations resulted in reduced cell
viability, axonal degeneration, electrophysiological
dysfunction and increased levels of phosphorylated c-Jun in
iPSC-DSN. Transcriptomic analyses revealed that the
upregulation of c-Jun strongly correlated with the
expression of genes of neuronal injury, apoptosis and
inflammatory signatures. To test whether c-Jun plays a
central role in the development of CIPN, we applied the
small molecule inhibitor of the Jun N-terminal kinase,
SP600125, to iPSC-DSN treated with neurotoxic chemotherapy.
c-Jun inhibition prevented chemotherapy-induced
neurotoxicity by preserving cell viability, axonal integrity
and electrophysiological function of iPSC-DSN. These
findings identify c-Jun as a key mediator of CIPN
pathophysiology across multiple drug types and present
preclinical evidence that c-Jun inhibition is an attractive
therapeutic target to prevent CIPN.},
cin = {AG Endres},
ddc = {610},
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:41233356},
pmc = {pmc:PMC12615653},
doi = {10.1038/s41420-025-02847-5},
url = {https://pub.dzne.de/record/282300},
}