A human iPSC-derived sensory neuron platform for high-throughput discovery of neuroprotectants against chemotherapy-induced peripheral neuropathy

  • Cell Rep Med. 2026 May 19;7(5):102787. doi: 10.1016/j.xcrm.2026.102787.
Veselina Petrova  1 ,  Caitlin E Mills  2 ,  Clemens Hug  3 ,  Aysel Cetinkaya-Fisgin  4 ,  Jennifer Splaine  5 ,  Sepideh Fouladzadeh  6 ,  Sara Hakim  1 ,  Rasheen Powell  1 ,  Shannon Zhen  7 ,  Mirra Chung  2 ,  Gary A Bradshaw  3 ,  Tao Deng  8 ,  Ilyas Singec  8 ,  Qing Wang  9 ,  Riki Kawaguchi  9 ,  Harathi Jonnagaddala  10 ,  Lee B Barrett  1 ,  Jennifer A Smith  5 ,  Marian Kalocsay  10 ,  Benjamin M Gyori  11 ,  Ahmet Hoke  4 ,  Peter K Sorger  2 ,  Clifford J Woolf  12
Affiliations
  • 1. F.M. Kirby Neurobiology Center, Program in Neurobiology, Boston Children's Hospital, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
  • 2. Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • 3. Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA.
  • 4. Department of Neurology, Neuromuscular Division, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 5. ICCB-Longwood Screening Facility, Harvard Medical School, 250 Longwood Avenue, Boston, MA, USA.
  • 6. Department of Bioengineering, Northeastern University, Boston, MA, USA.
  • 7. F.M. Kirby Neurobiology Center, Program in Neurobiology, Boston Children's Hospital, Boston, MA, USA.
  • 8. National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation, Stem Cell Translation Laboratory (SCTL), National Institutes of Health (NIH), Rockville, MD, USA.
  • 9. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
  • 10. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 11. Department of Bioengineering, Northeastern University, Boston, MA, USA; Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA.
  • 12. F.M. Kirby Neurobiology Center, Program in Neurobiology, Boston Children's Hospital, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
PMID: 42097147 DOI: 10.1016/j.xcrm.2026.102787
Abstract

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.

Keywords
STE20 kinases; axon degeneration; chemotherapy-induced peripheral neuropathy; high-throughput screening; iPSC-derived sensory neurons; neuroprotective small molecules.
Products