NNMT catalyzes the N-methylation of nicotinamide using S-adenosyl-L-methionine to produce N1-methylnicotinamide, representing a key vitamin B3 clearance pathway 123. The enzyme functions as a central metabolic regulator by depleting S-adenosyl-L-methionine, thereby limiting cellular methylation potential and causing widespread epigenetic changes through reduced histone methylation, particularly H3K27me3 and H3K9me3 45. In cancer contexts, NNMT exhibits tissue-specific expression patterns with complex roles. In cancer-associated fibroblasts (CAFs), NNMT acts as a master metabolic regulator where its depletion leads to H3K27me3 hypomethylation, driving complement secretion and immunosuppressive myeloid cell recruitment 64. However, NNMT can also negatively regulate metastasis-promoting properties in lung adenocarcinoma CAFs by preventing H3K4me3 hypermethylation and extracellular matrix remodeling gene upregulation 7. NNMT contributes to drug resistance mechanisms in non-small cell lung cancer by forming positive feedback loops involving EGR1 and lactate-mediated histone modifications 5. The enzyme also plays protective roles in heart failure by regulating the nicotinamide-NAD+ salvage pathway 8. These diverse functions establish NNMT as a promising therapeutic target across multiple diseases.