BHMT (betaine-homocysteine S-methyltransferase) is a cytosolic methyltransferase that catalyzes the remethylation of homocysteine to methionine using betaine as a methyl donor, producing dimethylglycine 1. This reaction is essential for homocysteine metabolism and contributes to S-adenosylmethionine (SAM) synthesis, the primary methyl group donor for cellular methylation reactions 2. Mechanistically, BHMT activity is regulated by phosphorylation at threonine 45 by the protein kinase RIMKLA, which activates BHMT to reduce homocysteine levels and suppress fatty acid synthesis gene expression 3. Beyond its cytosolic function, BHMT undergoes nutrient-dependent unconventional secretion from hepatocytes into plasma under specific metabolic conditions 4. Additionally, BHMT participates in autophagosome-lysosome fusion complexes, contributing to cellular radioresistance in glioblastoma through interaction with SDC1, TGM2, and FLOT1 5. In disease context, BHMT expression is significantly reduced in hepatocellular carcinoma (HCC) through abnormal splicing generating loss-of-function transcripts 2. BHMT alterations, reflected in differential ubiquitination levels, serve as prognostic biomarkers associated with aggressive HCC subtypes and poor survival 6. Conversely, BHMT activation ameliorates nonalcoholic fatty liver disease by suppressing hepatic lipid metabolism 3. Common BHMT genetic polymorphisms show functional variation in enzyme kinetics but lack significant association with coronary artery disease risk 17.