Identification of new targets for the protection against radiation-induced brain injury through integrated dual-omics analysis.

Background

Radiation-induced brain injury (RIBI) is a serious complication of cranial radiotherapy, yet its molecular mechanisms remain unclear. This study aimed to identify novel therapeutic targets for RIBI through integrated dual-omics analysis.

Methods

A mouse model of RIBI was established using 15 Gy of whole-brain X-ray irradiation. Behavioral tests and histopathological examinations were performed to validate cognitive dysfunction and neuronal damage. Hippocampal tissues were analyzed via transcriptomics and metabolomics to uncover key molecular changes.

Results

Transcriptomic analysis identified 29 significantly differentially expressed genes, including upregulated neuroinflammatory genes (Pcsk9, Ifi213) and downregulated neuroprotective factors (Tlx3, Irx1, Irx5), implicating exacerbated neuroinflammatory responses and impaired neurodevelopmental processes. Metabolomic profiling revealed 63 significantly altered metabolites, including elevated DNA oxidative damage markers and depleted branched-chain amino acids (BCAAs), suggesting mitochondrial dysfunction and increased oxidative stress. Integrated analysis highlighted correlations among neuroinflammation, DNA damage, and metabolic dysregulation, pointing to a potential interplay between these pathways.

Conclusions

This study demonstrates that RIBI pathogenesis involves synergistic interactions between neuroinflammation, DNA damage, and metabolic dysregulation. Targeting Pcsk9, enhancing DNA repair capacity, or supplementing BCAAs could represent potential neuroprotective strategies, although these correlative findings require functional validation. These findings provide a foundation for future studies on mitigating cognitive decline in patients receiving cranial radiotherapy.