Multifaceted role of serine hydroxymethyltransferase in health and disease

Serine hydroxymethyltransferase (SHMT) is a key enzyme in 1-carbon metabolism, a biochemical pathway critical for cellular growth, proliferation, and survival. One-carbon metabolism integrates the folate and methionine cycles to produce essential intermediates necessary for nucleotide synthesis, methylation reactions, and redox homeostasis. SHMT exists in 2 isoforms, SHMT1, which is localized in the cytoplasm, and SHMT2, which is localized in the mitochondria. SHMT1 and SHMT2 have distinct yet complementary functions. Both are involved in serine and glycine metabolism, ensuring a continuous supply of the 1-carbon units required for biosynthetic and epigenetic processes. SHMT dysregulation has been implicated in cancer progression and metabolic disorders, including cardiovascular diseases, diabetes, and neurological abnormalities. In cancer, the abnormal expression of SHMT has been associated with tumor growth, metabolic reprogramming, and treatment resistance, and has also been shown to correlate with poor patient outcomes. Considering its critical role in both cancer and metabolic diseases, SHMT has emerged as a potential therapeutic target in cancer. Recent studies have shown that SHMT inhibitors can reduce tumor proliferation and restore metabolic homeostasis. This review provides a comprehensive overview of the role of SHMT in the regulation of metabolic pathways and its role in tumor progression and metabolic diseases. In this review, we aimed to highlight the therapeutic potential of targeting SHMT and offer insights into the development of innovative treatment strategies in oncology and metabolic medicine. These insights support the hypothesis that targeting SHMT, particularly isoform-specific inhibition, may provide novel therapeutic avenues in both oncology and metabolic medicine.