Integrative multi-omics profiling implicates purine metabolism and the PI3K-Akt pathway in radiation-induced lung injury.

BACKGROUND

Thoracic radiotherapy commonly causes radiation-induced lung injury (RILI); however, its mechanisms remain poorly defined, and no FDA-approved therapies are available.

METHODS

To identify key pathways and regulators, we analyzed metabolic and transcriptomic alterations in a murine model of RILI. Following a 15 Gy thoracic irradiation, lung tissues were assessed by histopathology (H&E and Masson staining), LC-MS-based metabolomics, and transcriptomics.

RESULTS

Irradiated lungs showed erythrocyte exudation, inflammatory infiltration, fibrosis, and epithelial damage, whereas control tissues showed no pathological changes. Metabolomic profiling identified 186 differentially abundant metabolites, primarily enriched in purine and glycine/serine/threonine metabolism. Transcriptomics revealed 180 differentially expressed genes. Integrative analysis demonstrated that both metabolites and genes converged on the PI3K-Akt and phospholipase D signaling pathways, suggesting their potential as early RILI biomarkers. Analyses also revealed a consistent association between RILI and lung microbiota dysbiosis, pointing to novel mechanistic insights.

CONCLUSIONS

Our integrative multi-omics analysis reveals that RILI progression is characterized by dysregulated purine metabolism and transcriptomic changes that converge on the PI3K-Akt and phospholipase D signaling pathways. These pathway alterations were associated with lung microbiota dysbiosis, providing new avenues for early biomarker discovery and therapeutic intervention.