Metabolomic effects of total flavone of Abelmoschus manihot (L.) medik. on patients with radiation-induced heart disease.

Radiation-induced heart disease (RIHD) is a severe complication of thoracic radiotherapy. Total flavone of Abelmoschus Manihot (L.) Medik. (TFA) demonstrates therapeutic potential on RIHD. However, its metabolic mechanisms remain elusive. This study aims to elucidate the change of serum metabolic profile of RIHD treated with TFA and identify potential metabolic pathways for mitigating irradiation damage. We randomly divided 100 RIHD patients into two groups, (1) TFA group: patients receiving TFA intervention (n = 50) and (2) non-TFA group: the other not receiving intervention (n = 50). The serum of patients was collected separately after the treatment. GC-MS metabolomics analysis employed to investigate differential metabolites in the serum of these patients. Multivariate (PCA/OPLS-DA) and univariate analyses identified differentially abundant metabolites (VIP > 1.0, p < 0.05, FC > 1.2) and enriched pathways. The non-TFA group exhibited profound metabolic disturbances characterized by mitochondrial dysfunction (depleted citrate with accumulated succinate/lactate), amino acid imbalance (elevated phenylalanine/tyrosine/tryptophan alongside reduced arginine and disrupted arginine-citrulline ratio), and lipotoxic stress (accumulated long-chain fatty acids including palmitic/arachidic acid with ketone body dysregulation). TFA intervention significantly reversed these perturbations: it restored citric acid cycle homeostasis through attenuated depletion of citrate and reduced succinate/lactate accumulation; rebalanced amino acid metabolism by lowering aromatic amino acids, elevating arginine levels to normalize the arginine/citrulline axis, and enhancing glycine/serine/threonine flux; and ameliorated lipid dysregulation via suppression of long-chain fatty acids and stabilization of ketone bodies. Pathway analysis confirmed that TFA can significantly regulate citric acid cycle, arginine biosynthesis, and fatty acid β-oxidation pathways. This study provides the first evidence that TFA counteracts RIHD metabolic pathology through coordinated mechanisms: TFA can repair mitochondrial dysfunction by restoring TCA cycle intermediates and reducing ROS generation. Meanwhile, TFA can reinforce redox defense by the inhibition of proteolysis-derived aromatic amino acids and the support of glutathione-precursor metabolism. Additionally, TFA can attenuate vascular injury by suppressing lipotoxicity while promoting endothelial NO synthesis.