Petrova Elizaveta¹, Suzuki Haruto², Zunaira Fatima³, Soares Rodrigo⁴, Neumann Julian⁵, Lambert Chloé⁶
ABSTRACT:
Background: One-carbon (1C) metabolism is a highly conserved metabolic network that integrates folate and methionine cycles to support essential cellular functions, including nucleotide synthesis, methylation reactions, and redox balance. As a central node linking nutrient availability to epigenetic and proliferative outputs, 1C metabolism plays a pivotal role in embryogenesis, immune activation, tissue regeneration, and oncogenesis. Dysregulation of this pathway contributes to developmental abnormalities, cancer progression, and therapeutic resistance. Methods and Results: This review delineates the biochemical architecture of one-carbon metabolism, emphasizing its compartmentalization between cytosolic and mitochondrial arms and its dynamic regulation by nutrient cues and signaling pathways. Serine and glycine act as primary donors of 1C units, which are transferred via tetrahydrofolate derivatives to fuel purine and thymidylate biosynthesis and generate S-adenosylmethionine (SAM), the universal methyl donor. SAM availability directly governs the activity of DNA methyltransferases, histone methyltransferases, and RNA methylation enzymes, thereby influencing gene expression, chromatin state, and cellular identity. Metabolic flux through 1C pathways is tightly coupled to proliferative demand, with increased activity observed in rapidly dividing cells such as stem cells, activated lymphocytes, and cancer cells. Integration of transcriptomic, metabolomic, and epigenomic data has revealed tissue- and context-specific roles of 1C flux, highlighting its plasticity and relevance across physiological and pathological states. Conclusion: One-carbon metabolism serves as a metabolic-epigenetic interface that translates nutrient inputs into heritable and proliferative cellular outcomes. Understanding its regulation and context-dependent rewiring offers new opportunities for precision targeting in cancer, regenerative medicine, and metabolic diseases.