Veselina Petrova, Caitlin E. Mills, Clemens Hug, Aysel Cetinkaya‐Fisgin, Jen Splaine, Sepideh Fouladzadeh, Sara Hakim, Rasheen Powell, Shannon Zhen, Mirra Chung, Gary A. Bradshaw, Tao Deng, Ilyas Singeç, Q Wang, Riki Kawaguchi, Harathi Jonnagaddala, Lee B. Barrett, Jennifer A. Smith, Marian Kalocsay, Benjamin M. Gyori, Ahmet Höke, Peter K. Sorger, Clifford J. Woolf
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.