Serine Hydroxymethyltransferase (SHMT) in biology and disease: molecular mechanisms and therapeutic targeting

Serine Hydroxymethyltransferase 1 and 2 (SHMT1/2), as key enzymes in folate metabolism, regulate diverse physiological processes through one-carbon metabolism, including nucleotide biosynthesis, methylation reactions, and redox homeostasis. As a form of metabolic reprogramming, dysregulated SHMT-mediated one-carbon metabolism has been increasingly reported in various human cancers and liver metabolic diseases. Therefore, a concise review of its regulatory roles and disease-associated functions is necessary to clarify its biological and translational significance. This review summarizes the molecular functions of SHMT1/2, with particular emphasis on their central roles in the folate-methionine cycle and serine-glycine metabolic pathway. Beyond their canonical enzymatic activities, SHMT1/2 also exhibit critical non-enzymatic functions. Their activity is tightly regulated by transcription factors and post-translational modifications. SHMT1/2 play significant roles in multiple pathological conditions and are implicated in the initiation and progression of various cancers, such as ovarian, lung, liver, gastric, colorectal, and renal carcinomas. Moreover, SHMT-mediated one-carbon metabolism critically influences liver diseases (e.g., non-alcoholic fatty liver disease, steatohepatitis), inflammatory disorders (e.g., skin inflammation, osteoarthritis), and neurological diseases (e.g., schizophrenia, hypomyelinating leukodystrophy, stroke). Finally, this review discusses the clinical translational potential of SHMT inhibitors in cancer-targeted therapies, offering a theoretical basis for expanding the therapeutic applications of SHMT1/2 in diseases associated with dysregulated one-carbon metabolism. SHMT1/2 regulate diseases associated with dysregulated one-carbon metabolism through both their enzymatic and non-enzymatic functions. Particularly in cancer, they function as either oncogenes or tumor suppressors in a context-dependent manner, holding significant potential as diagnostic, prognostic, and therapeutic targets.