Time-resolved lipidomic atlas of the murine lung response to acute ionizing radiation

Abstract The lung is among the most radiosensitive organs and a principal dose-limiting organ in thoracic radiotherapy, yet the acute metabolic consequences of irradiation at the lipidomic level remain poorly characterized. We constructed a time-resolved lipidomic atlas of the murine lung response to high-dose irradiation. Male C57BL/6 J mice received a single 10 Gy whole-body X-ray dose, and lungs were collected at 5 minutes, 1 hour, 4 hours, and 24 hours post-exposure (n = 5 per group) and analyzed by untargeted liquid chromatography–tandem mass spectrometry. Radiation triggered rapid and coordinated lipid remodeling. Principal component analysis revealed a structured temporal trajectory, and oxidized lipid species increased significantly by 24 hours. Pulmonary surfactant lipids, including dipalmitoylphosphatidylcholine and phosphatidylglycerol, underwent early and progressive oxidation. Membrane signaling lipids shifted in a manner consistent with a transient pro-survival bias, with ceramide depletion, sphingomyelin accumulation, and phosphatidylserine oxidation. Mitochondrial lipids displayed a coordinated triad of early cardiolipin oxidation, progressive coenzyme Q depletion, and sustained phosphatidylethanolamine accumulation. Lysobisphosphatidic acid accumulated steadily, consistent with endolysosomal activation, while storage triglycerides and diglycerides were rapidly mobilized and free fatty acids accumulated at later time points. Class-level changes were temporally ordered and compartmentally organized, indicating that the acute lipid response is not confined to oxidative damage. The lipid classes involved overlap with those implicated in ferroptosis, mitophagy, lipophagy, and surfactant biology, although these processes were not assessed directly here. This atlas is offered as a descriptive resource for mechanistic study of radiation-induced lung injury.