Early Pathology of Radiation-Induced Brain Injury Revealed by Integrated Proteomic and Metabolomic Analysis

Background/Objectives: Radiation-induced brain injury (RIBI) remains a major clinical complication in patients with head and neck malignancies undergoing radiotherapy. Late-delayed pathological manifestations including cognitive decline, brain atrophy and dementia emerge after irradiation of normal brain tissue. Multiple overlapping signaling pathways hinder the identification of effective early diagnostic biomarkers and therapeutic targets for RIBI. This study aimed to explore early molecular alterations within 24 h post-radiation and discover potential circulating biomarkers for early RIBI recognition. Methods: We utilized an integrated proteomic and metabolomic strategy to profile early molecular changes 24 h after radiation exposure. Plasma and serum samples from mice or human patients following gamma-ray brain exposure were analyzed to detect circulating dsDNA levels, serum proteins, and metabolites. Dose-dependent responses of protein and molecules were further characterized. Conclusions: Multi-omics profiling revealed acute systemic molecular perturbations immediately after radiation. DNA lesions induced by irradiation led to elevated plasma dsDNA, activated the cytosolic DNA sensing pathway and the acute inflammatory response pathway, and disrupted the glutamate–glutamine cycle. These are all important mechanisms among the early significant changes in the circulatory system after gamma-ray brain exposure. Plasma dsDNA, together with serum SAA, MMP9 and Glu-Met, represent promising circulating markers that reflect early RIBI pathology, providing clues for the early diagnosis and mechanistic investigation of radiation-induced brain injury.