Local production of reactive oxygen species drives vincristine-induced axon degeneration

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious consequence of cancer treatment that causes autonomic, motor, and sensory deficits, often resulting in severe pain. CIPN progression frequently leads to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Furthermore, as much of our knowledge on how CIPN develops derives from rodent studies with uncertain translatability, studying it in human neurons is critical. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology leading from elevated axonal ROS levels to mitochondrial dysfunction and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mdivi-1, identifying a novel therapeutic avenue to treat CIPN.