NNMT catalyzes the N-methylation of nicotinamide and related pyridines using S-adenosyl-L-methionine as the universal methyl donor, producing N1-methylnicotinamide. This reaction comprises a predominant nicotinamide/vitamin B3 clearance pathway and plays a central role in regulating cellular methylation potential by consuming S-adenosyl-L-methionine and limiting its availability for other methyltransferases. Through its consumption of S-adenosyl-L-methionine, NNMT drives genome-wide epigenetic and transcriptional changes by reducing repressive histone marks such as H3K27me3. In developmental contexts, NNMT contributes to the low levels of repressive histone marks characteristic of pluripotent embryonic stem cells. NNMT also regulates metabolic processes in white adipose tissue and hepatic gluconeogenesis and cholesterol biosynthesis, and its product N1-methylnicotinamide regulates hepatic protein acetylation by increasing SIRT1 stability. Clinically, NNMT has emerged as a critical driver of cancer progression and immunosuppression. In cancer-associated fibroblasts, NNMT-induced H3K27me3 hypomethylation drives complement secretion and recruits immunosuppressive myeloid-derived suppressor cells, while NNMT inhibition restores CD8+ T cell activation and immune checkpoint blockade efficacy across ovarian, breast, and colon tumor models 1. NNMT overexpression promotes acquired EGFR-TKI resistance in non-small cell lung cancer through EGR1 and lactate-mediated feedback loops, and NNMT inhibitors combined with osimertinib show promise for overcoming this resistance 2. High NNMT expression in colorectal cancer pericytes promotes metastasis by facilitating circulating tumor cell–neutrophil cluster formation via CXCL5/CXCR2 signaling 3. Beyond cancer, NNMT suppression by indole-3-propionic acid protects against heart failure with preserved ejection fraction by restoring the nicotinamide–NAD+ salvage pathway and SIRT3 levels 4.