GNMT and Its Regulatory MicroRNAs as Biomarkers and Therapeutic Targets for Metabolic Dysfunction-Associated Fatty Liver Disease and Hepatocellular Carcinoma.

Glycine N-methyltransferase (GNMT), a S-adenosylmethionine (SAM)-dependent methyltransferase, is primarily expressed in the liver and plays a key role in regulating liver metabolism and protecting against liver injury. Several studies have shown that deficiency or downregulation of GNMT is strongly associated with the pathogenesis of hepatocellular carcinoma (HCC), highlighting its critical role as a tumor suppressor. Other studies have shown that GNMT is also strongly correlated with the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). Although many factors regulate GNMT expression, recent studies have identified microRNAs (miRNAs), such as miR-873-5p and miR-224, as key post-transcriptional regulators that directly target GNMT mRNA and suppress its expression in HCC and MAFLD. This review provides an overview of GNMT's role in liver physiology and how its dysregulation contributes to the progression of HCC and MAFLD, with a focus on the regulation of GNMT by miR-873-5p and miR-224. We also highlight the potential of these two miRNAs as biomarkers and therapeutic targets for HCC and MAFLD, discussing emerging strategies such as antisense-based inhibition, gene therapy, and small-molecule inducers aimed at restoring GNMT expression.