Lithium for Radiation-Induced Damage in Pediatric Brain Tumors: Preclinical Evidence and Clinical Perspectives

Central nervous system (CNS) tumors account for nearly one third of pediatric cancers and remain the leading cause of cancer-related mortality in children. Cranial radiotherapy is a cornerstone of treatment for many high-grade and embryonal brain tumors, often in combination with surgery and chemotherapy. However, improved survival has been accompanied by a growing burden of late neurocognitive, emotional, social, and endocrine sequelae. Damage to hippocampal neural stem and progenitor cells partly drives radiation-induced cognitive decline, which leads to reduced neurogenesis and increased gliogenesis. Lithium has emerged as a promising strategy to protect or repair the irradiated brain through its neuroprotective, anti-inflammatory, anti-apoptotic, and pro-neurogenic effects. Preclinical evidence supports its potential to mitigate radiation-induced brain injury. In cellular models, lithium appears to protect neural progenitors and hippocampal neurons from irradiation-related damage but does not confer comparable protection to tumor cells. In juvenile rodent models, lithium administration before, during, or after cranial irradiation has been associated with reduced apoptosis in hippocampal neurogenic regions, preservation or restoration of neurogenesis, attenuation of neuroinflammation, and improvement of cognitive and behavioral outcomes. Importantly, delayed lithium treatment has also shown restorative effects, indicating a potential role as a neuroregenerative strategy for survivors with late effects. Mechanistically, these benefits appear to arise from modulation of apoptotic pathways, GSK-3β-related signaling, neurogenic cell fate, and epigenetic programs that promote neuronal differentiation over gliogenesis. These data have provided the rationale for early clinical translation and ongoing trials now assessing whether lithium can improve neurocognitive outcomes after cranial radiotherapy in pediatric brain tumor patients. This narrative review summarizes the preclinical basis and emerging clinical evidence for lithium as a potential adjunct to radiotherapy while discussing key unresolved issues, including optimal timing, treatment duration, tumor safety, and patient selection.