c-Jun inhibition mitigates chemotherapy-induced neurotoxicity in iPSC-derived sensory neurons

TL;DR

This study shows that blocking c-Jun can reduce nerve damage caused by chemotherapy in lab-grown human neurons.

Contribution

The study identifies c-Jun as a key mediator of chemotherapy-induced neurotoxicity and suggests its inhibition as a potential treatment.

Findings

Chemotherapy drugs caused reduced cell viability, axonal degeneration, and increased phosphorylated c-Jun in iPSC-derived sensory neurons.

c-Jun inhibition preserved cell viability, axonal integrity, and electrophysiological function in neurons exposed to chemotherapy.

Transcriptomic analysis linked c-Jun upregulation to neuronal injury, apoptosis, and inflammation genes.

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.

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