A human iPSC-derived sensory neuron platform for high-throughput discovery of neuroprotectants against chemotherapy-induced peripheral neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of cancer treatment, yet the lack of predictive human models continues to hinder therapeutic progress. Here, we establish a scalable and reproducible model of paclitaxel-induced axon degeneration and neurotoxicity in human iPSC-derived sensory neurons, suitable for high-throughput identification of neuroprotective compounds. Using this platform, we screen a library of 192 kinase inhibitors and identify 19 hits that commonly inhibit three STE20 kinases-MAP4K4, MINK1, and TNIK. Genetic knockdown studies reveal that multi-kinase inhibition of these kinases is required for neuroprotection against paclitaxel. Consistently, selective pharmacological inhibition of the identified STE20 kinases rescues paclitaxel-induced axon degeneration in iPSC-derived sensory neurons and primary human dorsal root ganglia (DRG) and preserves intraepidermal nerve fiber density in a mouse model of CIPN. Together, these findings establish a translational human sensory neuron platform that enables target validation and drug discovery for CIPN.
Authors
- Mirra Chung (ORCID: https://orcid.org/0000-0002-4033-7930)
- Benjamin M. Gyori (ORCID: https://orcid.org/0000-0001-9439-5346)
- Q Wang
- Rasheen Powell (ORCID: https://orcid.org/0000-0003-4423-6413)
- Ahmet Höke (ORCID: https://orcid.org/0000-0003-1215-3373)
- Ilyas Singeç (ORCID: https://orcid.org/0000-0003-3941-1838)
- Veselina Petrova (ORCID: https://orcid.org/0000-0002-5593-0198)
- Shannon Zhen (ORCID: https://orcid.org/0009-0007-7446-3074)
- Aysel Cetinkaya‐Fisgin (ORCID: https://orcid.org/0000-0002-0557-7963)
- Peter Karl Sorger (ORCID: https://orcid.org/0000-0002-3364-1838)
- Riki Kawaguchi (ORCID: https://orcid.org/0000-0002-2489-4825)
- Marian Kalocsay (ORCID: https://orcid.org/0000-0002-4187-5829)
- Jen Splaine
- Harathi Jonnagaddala
- Sepideh Fouladzadeh
- Lee B. Barrett
- Caitlin E. Mills
- Clemens Hug
- Jennifer A. Smith
- Gary A. Bradshaw
- Clifford J. Woolf (ORCID: https://orcid.org/0000-0002-6636-3897)
- Sara Hakim
- Tao Deng
Institutions
- Boston Children's Hospital (US)
- Northeastern University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Longwood University (US)
- Johns Hopkins University (US)
- University of California, Los Angeles (US)
- Johns Hopkins Medicine (US)
- National Center for Advancing Translational Sciences (US)
- Center for Systems Biology (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2026-05-01
- DOI
- https://doi.org/10.1016/j.xcrm.2026.102787
- Primary Topic
- Cancer Treatment and Pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institute of Neurological Disorders and Stroke
- Defense Sciences Office, DARPA