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000282300 1001_ $$00000-0002-0183-8177$$aHew, Lois$$b0
000282300 245__ $$ac-Jun inhibition mitigates chemotherapy-induced neurotoxicity in iPSC-derived sensory neurons.
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000282300 520__ $$aChemotherapy-induced peripheral neuropathy (CIPN) affects up to two-thirds of cancer patients undergoing cytotoxic chemotherapy. Here, we used human iPSC-derived sensory neurons (iPSC-DSN) to model CIPN in vitro. Administration of various chemotherapeutic agents (i.e., paclitaxel, vincristine, bortezomib and cisplatin) at clinically applicable concentrations resulted in reduced cell viability, axonal degeneration, electrophysiological dysfunction and increased levels of phosphorylated c-Jun in iPSC-DSN. Transcriptomic analyses revealed that the upregulation of c-Jun strongly correlated with the expression of genes of neuronal injury, apoptosis and inflammatory signatures. To test whether c-Jun plays a central role in the development of CIPN, we applied the small molecule inhibitor of the Jun N-terminal kinase, SP600125, to iPSC-DSN treated with neurotoxic chemotherapy. c-Jun inhibition prevented chemotherapy-induced neurotoxicity by preserving cell viability, axonal integrity and electrophysiological function of iPSC-DSN. These findings identify c-Jun as a key mediator of CIPN pathophysiology across multiple drug types and present preclinical evidence that c-Jun inhibition is an attractive therapeutic target to prevent CIPN.
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000282300 7001_ $$aMaierhof, Smilla K$$b1
000282300 7001_ $$aIvanov, Andranik$$b2
000282300 7001_ $$aBeule, Dieter$$b3
000282300 7001_ $$aFernandez Vallone, Valeria$$b4
000282300 7001_ $$00000-0002-9283-4605$$aStachelscheid, Harald$$b5
000282300 7001_ $$00000-0001-5645-2557$$aFrahm, Silke$$b6
000282300 7001_ $$aTelugu, Narasimha Swamy$$b7
000282300 7001_ $$0P:(DE-2719)2811033$$aEndres, Matthias$$b8$$eLast author
000282300 7001_ $$00000-0001-7195-3894$$aBoehmerle, Wolfgang$$b9
000282300 7001_ $$00000-0002-6825-7270$$aHuehnchen, Petra$$b10
000282300 7001_ $$00000-0003-0199-9672$$aSchinke, Christian$$b11
000282300 773__ $$0PERI:(DE-600)2842546-7$$a10.1038/s41420-025-02847-5$$gVol. 11, no. 1, p. 529$$n1$$p529$$tCell death discovery$$v11$$x2058-7716$$y2025
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