Glutamine, a Potential Metabolomic Biomarker and Therapeutic Target in Radiation-induced Liver Damage

Radiation-induced liver damage (RILD) significantly limits the clinical application of radiotherapy for upper abdominal malignancies. Radiation can induce metabolic disorder in liver tissues. However, there is no systematic research on the effects of radiation on liver metabolism. In this study, we collected time-series liver tissue samples from irradiated rats at multiple time points, from 3 days to 4 weeks after exposure, to reveal dynamic alterations in metabolic profiles throughout RILD progression. Acetylcholic acid, p-hydroxyphenyl-lactic acid, ascorbic acid, daidzein, and glutamine (Gln) were identified as potential biomarkers, demonstrating good diagnostic sensitivity and specificity. As a metabolomic biomarker, Gln emerged as a potential metabolic target based on pathway enrichment analysis, which could modulate the radiosensitivity of both mouse (JS-1) and human (LX-2) hepatic stellate cells. Transcriptomics, co-immunoprecipitation (Co-IP) and functional rescue experiments demonstrated that the regulation of radiosensitivity by Gln is mediated through the Col1α2/ITGB1/AKT signaling axis. In the mouse RILD model, Gln prevented irradiation-induced body weight loss, preserved liver structure, and reduced TGF-β and TNF-α expression as well as collagen deposition. L-alanyl-glutamine (Ala-Gln) and liposomes were introduced to further enhance the radioprotective effects of Gln. This study provides the necessary theoretical and experimental basis for diagnosis and intervention of RILD.