Myelodysplastic syndromes (MDS) are hematologic malignancies characterized by ineffective hematopoiesis and high risk of progression to acute myeloid leukemia (AML). Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, exhibits anti-cancer effects through diverse mechanisms, including metabolic modulation.

This study assessed EGCG-induced metabolic alterations in a transgenic MDS mouse model using untargeted metabolomics.

C57BL/6-Tg(Vav1-NUP98/HOXD13) mice were treated for 30 days with EGCG (50 mg/kg/day, intraperitoneally) or saline (control). Serum samples were analyzed by LC-ESI-QToF-MS in positive and negative ionization modes. Data processing (Progenesis™ QI) and statistical analysis (MetaboAnalyst™ 5.0) included PCA, VIP score ranking, and KEGG-based pathway enrichment.

From 3,910 detected features, 72 metabolites were identified—predominantly glycerophospholipids, fatty acids, and steroids. PCA revealed distinct metabolic profiles between groups. Seven significantly altered pathways were identified, including unsaturated fatty acid biosynthesis, amino acid metabolism (alanine, aspartate, glutamate, glycine, serine, and threonine), and ketone body synthesis/degradation. Elevated β-hydroxybutyrate suggested enhanced fatty acid β-oxidation and a metabolic shift from glycolysis toward lipid-based energy production.

EGCG treatment in MDS mice induced broad metabolic reprogramming, reducing unsaturated fatty acid synthesis while enhancing β-oxidation and ketogenesis—conditions less favorable to glycolysis-dependent neoplastic cells (Warburg effect). These changes may lower membrane fluidity, disrupt signaling pathways, restrict nucleotide biosynthesis, and modulate epigenetic regulation via one-carbon metabolism. Such metabolic stress could contribute to EGCG’s anti-cancer activity by impairing tumor cell proliferation and survival. Further preclinical and translational studies are warranted to confirm these mechanisms and explore EGCG’s potential as a metabolic modulator and adjuvant therapy in MDS and related hematologic malignancies.