TY  - JOUR
AU  - Hew, Lois
AU  - Maierhof, Smilla K
AU  - Ivanov, Andranik
AU  - Beule, Dieter
AU  - Fernandez Vallone, Valeria
AU  - Stachelscheid, Harald
AU  - Frahm, Silke
AU  - Telugu, Narasimha Swamy
AU  - Endres, Matthias
AU  - Boehmerle, Wolfgang
AU  - Huehnchen, Petra
AU  - Schinke, Christian
TI  - c-Jun inhibition mitigates chemotherapy-induced neurotoxicity in iPSC-derived sensory neurons.
JO  - Cell death discovery
VL  - 11
IS  - 1
SN  - 2058-7716
CY  - London
PB  - Nature Publishing Group
M1  - DZNE-2025-01270
SP  - 529
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:41233356
C2  - pmc:PMC12615653
DO  - DOI:10.1038/s41420-025-02847-5
UR  - https://pub.dzne.de/record/282300
ER  -