Transcriptional profiling uncovers microglial HIF-1α signaling as a therapeutic target of radiation-induced brain injury.

Cranial irradiation is a widely used therapeutic modality for brain tumors but is frequently associated with long-term neurological complications, including cognitive deficits and mood disturbances. Despite its clinical relevance, the cellular and molecular mechanisms underlying radiation-induced brain injury (RIBI) remain poorly understood. In this study, we employed single-cell RNA sequencing to elucidate cell-type-specific transcriptional changes following cranial irradiation in mice. Irradiated animals exhibited marked microglial alterations, including a dynamic shift toward a pathologically activated state, alongside significant impairments in hippocampus-dependent cognitive dysfunction. Notably, we identified a radiation-induced upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) signaling specifically within microglial populations, which was not detectable using conventional bulk analyses. Pharmacological inhibition of HIF-1α with 2-methoxyestradiol led to partial recovery of cognitive function and selectively suppressed the expression of Ccl2, a key HIF-1α-associated chemokine implicated in neuroinflammatory signaling. These findings highlight the subtype-specific vulnerability of microglia to radiation and underscore the central role of HIF-1α-mediated transcriptional changes in RIBI. Targeting the microglial HIF-1α-Ccl2 axis may thus offer a promising strategy to mitigate late-onset cognitive dysfunction following cranial irradiation.