Chemotherapy induces multiple sclerosis-like neuropathologies that can be rescued by clobetasol

Chemotherapy is essential for cancer management yet frequently accompanied with adverse effects, particularly for temozolomide (TMZ), a frontline chemotherapeutic agent for glioma. Although clinical neurological abnormalities linked to TMZ have been observed, mechanisms underlying TMZ-induced neural impairments remain poorly understood, and effective interventions are lacking. Here, we demonstrated that TMZ chemotherapy induced neurodegenerations that recapitulated pathological features of multiple sclerosis, including demyelination, neuroinflammation and axonal degeneration. In adolescent mice, TMZ treatment resulted in severe white matter damage that spontaneously recovered, whereas in adult mice, moderate myelin damage persisted without recovery within the same timeframe. Importantly, we identified that clobetasol effectively reversed TMZ-induced white matter damage and trends toward anxiety and depression in adult mice by suppressing TMZ-induced AMPK activation and attenuating neuroinflammation, thereby promoting remyelination. Our findings reveal the previously underappreciated neural toxicities associated with TMZ chemotherapy and highlight the therapeutic efficacy of clobetasol in mitigating chemotherapy-induced neural impairment, providing a strategy to enhance the life quality of cancer patients.