The aberration of key amino acids participated one-carbon metabolism may jeopardize genetic stability in cancer development.

One-carbon (1C) metabolism, primarily orchestrated by key amino acids, serves as a fundamental biochemical hub that sustains diverse physiological functions, especially genetic stability. Given the indispensable role of 1C units in providing building blocks, redox donors, and methyl donors for genomic integrity, deficiencies in 1C-associated amino acids have been proposed to disrupt genome maintenance and potentially promote oncogenic alterations. Such disruptions are suggested to create a permissive environment for oncogenesis, driving epigenetic chaos and gene mutations, which may in turn exacerbate metabolic imbalance. This review comprehensively summarizes the multifaceted roles of 1C metabolism in cellular physiology, with a focus on its function in nucleotide and protein biosynthesis, integrated maintenance of redox equilibrium, and methylation-dependent chromatin remodeling. Special emphasis is placed on elucidating the genetic-level mechanisms through which 1C metabolism influences cancer initiation and progression. Based on systematic analysis of these interconnected pathways, we highlight how dysregulation of 1C metabolism contributes to tumorigenesis, especially through impaired nucleotide synthesis and compromised DNA integrity. Finally, we discuss the emerging therapeutic potential of targeting 1C metabolic pathways in cancer, particularly from the perspective of restoring genomic stability.