P7C3-A20 prevents whole brain radiotherapy-induced chronic hippocampal redox imbalance and neuropsychiatric impairment in mice.

Whole brain radiotherapy (WBRT) prolongs survival for patients with brain metastases but produces persistent oxidative injury to the brain and long-term neuropsychiatric sequelae, for which no approved neuroprotective therapies exist. Here, we show that a single course of WBRT produces chronic oxidative stress in mice that persists for at least one year, equivalent to decades in humans, and selectively injures the hippocampus, causing cognitive decline and depressive-like behavior. Daily administration of P7C3-A20, a neuroprotective compound that stabilizes brain nicotinamide adenine dinucleotide (NAD+) homeostasis, markedly reduced oxidative stress and prevented hippocampal pathology for one year after WBRT. P7C3-A20 treatment suppressed neuroinflammation, axonal injury, loss of hippocampal neural precursor cells, blood-brain barrier breakdown, and microglial lipid droplet accumulation, resulting in long-term preservation of cognition and brain health. Crucially, P7C3-A20 did not impair the antitumor efficacy of radiation. These findings identify NAD+ homeostasis stabilization as a promising strategy to mitigate radiation-induced oxidative damage and to prevent long-term neuropsychiatric complications of WBRT.