Metformin inhibits the histone methyltransferase CARM1 and attenuates H3 histone methylation during gluconeogenesis.

Hyperglycemia is a hallmark of metabolic disorders, yet the precise mechanisms linking epigenetic regulation to glucose metabolism remain underexplored. Coactivator-associated arginine methyltransferase 1 (CARM1), a type I histone methyltransferase, promotes transcriptional activation through the methylation of histone H3 at arginine residues H3R17 and H3R26. Here, we identify a novel mechanism by which metformin, a widely prescribed antidiabetic drug, inhibits CARM1 activity. Using biochemical and biophysical assays, we show that metformin binds to the substrate-binding site of CARM1, reducing histone H3 methylation levels in CARM1-overexpressing hepatic cells and liver tissues from metformin-fed mice. This epigenetic modulation suppresses the expression of gluconeogenic enzymes (G6Pase, FBPase, and PCK1), thereby reversing CARM1-induced glycolytic suppression and regulating gluconeogenesis. Importantly, metformin does not alter CARM1 protein levels and its recruitment to gluconeogenic gene promoters but diminishes H3R17me2a marks at these loci. Our findings reveal a previously unrecognized epigenetic mechanism of metformin action, offering new therapeutic insights for hyperglycemia management.