Radical hemithoracic radiotherapy (RHRT) offers a promising approach to extend survival in patients with malignant pleural mesothelioma. In this study, we examined how RHRT influences the systemic metabolic profile and whether these changes correlate with clinical outcomes. Nineteen patients underwent RHRT at 50 Gy delivered over 25 fractions. Serum metabolite levels were analyzed before and after treatment using targeted liquid chromatography-tandem mass spectrometry. Statistical modeling, including OPLS-DA and PLS regression, was used to identify treatment-induced metabolomic shifts and their relationship with overall survival. RHRT was associated with marked reductions in multiple metabolite classes, including citrulline and taurine, C14, C18:1, and C18:2 acyl-carnitines, and several unsaturated long-chain phosphatidylcholines (PC ae 42:5, PC ae 44:5, PC ae 44:6). Pathway analysis indicated that arginine metabolism and polyamine synthesis were the most affected. Notably, alterations in amino acids and acyl-carnitines explained approximately 60% of the variability in overall survival among patients. These results suggest that RHRT exerts profound systemic metabolic effects, some of which may serve as predictive biomarkers. Incorporating metabolomic profiling into the clinical management of malignant pleural mesothelioma may enhance patient stratification and guide personalized treatment decisions.
