Shmt2, or serine hydroxymethyltransferase 2, is a key enzyme in one-carbon metabolism. It uses pyridoxal-5'-phosphate (PLP) as a cofactor and can convert serine into glycine and a tetrahydrofolate-bound one-carbon unit, ultimately supporting thymidine and purine synthesis [2,3]. This process is crucial for amino acid and nucleotide metabolism, and is associated with multiple biological processes and disease conditions.

In disease-related studies, hepatocyte-specific ablation of Shmt2 in mice (KO model) showed that its absence increased serine and glycine levels in circulation, decreased liver methylation potential, and increased susceptibility to fatty liver disease. However, when fed a high-fat, fructose, and cholesterol diet, these mice had less inflammation and fibrosis, highlighting its stage-specific functions in non-alcoholic fatty liver disease (NAFLD) pathogenesis [4]. In Burkitt lymphoma, inhibition of Shmt2 (by knockdown or pharmacological compounds) led to anti-lymphoma effects both in vitro and in vivo. It reduced intracellular glycine and formate levels, inhibited the mTOR pathway, and triggered autophagic degradation of the oncogenic transcription factor TCF3, collapsing tonic B-cell receptor (BCR) signaling essential for lymphoma cell survival [1].

In conclusion, Shmt2 is essential for one-carbon metabolism, playing a role in nucleotide and amino acid synthesis. Through gene knockout models in mice, its functions in diseases like NAFLD and Burkitt lymphoma have been revealed. These studies help us understand its role in disease mechanisms, potentially providing new targets for therapeutic intervention.