Nicotinamide N-Methyltransferase Metabolism in Cancer and Metabolic Disorders

Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine (SAM) to nicotinamide, yielding 1-methylnicotinamide (1-MNA) and S-adenosylhomocysteine. By linking NAD+ metabolism with methyl donor availability, NNMT occupies a central position in cellular redox balance, one-carbon metabolism and epigenetic regulation. In oncology, elevated NNMT expression is observed in diverse tumour types, where it supports proliferative signalling, remodels the tumour microenvironment and contributes to chemoresistance. In metabolic disorders, NNMT overactivation depletes NAD+, impairs sirtuin activity and disrupts methylation capacity, driving fatty liver disease, insulin resistance and obesity. These multifaceted roles render NNMT both a biomarker of disease progression and a promising therapeutic target. Emerging strategies to modulate NNMT—genetic, biochemical and pharmacological—offer new avenues for intervention in cancer and metabolic syndrome.

Research from Nature Portfolio

Recent studies have dissected how NNMT overactivation drives metabolic dysfunction in the liver and how its inhibition can restore homeostasis. In transgenic models overexpressing NNMT, a high-fat diet supplemented with nicotinamide leads to pronounced hepatic steatosis, fibrosis and inflammation, underpinned by NAD+ depletion and reduced SIRT3 deacetylase activity that impairs fatty acid oxidation. Concomitant loss of methylation capacity enhances connective tissue growth factor expression, promoting fibrotic remodelling. Complementary work has characterised a small-molecule analogue of nicotinamide that acts as a slow-turnover substrate, sustaining NNMT inhibition. In obese rodent models, treatment lowers plasma 1-MNA, improves insulin sensitivity, normalises glucose tolerance and induces weight loss, validating NNMT as a target in metabolic disease.

Nicotinamide N-Methyltransferase Metabolism in Cancer and Metabolic Disorders publication trend

The graph below shows the total number of articles in nicotinamide n-methyltransferase metabolism in cancer and metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Nicotinamide N-methyltransferase (NNMT): An enzyme that transfers a methyl group from S-adenosylmethionine to nicotinamide, linking NAD+ metabolism with methyl donor pathways.

1-Methylnicotinamide (1-MNA): The methylated product of NNMT activity, which can act as a signalling metabolite influencing cell cycle and redox balance.

Nicotinamide adenine dinucleotide (NAD+): A coenzyme central to redox reactions, DNA repair and sirtuin-mediated deacetylation.

S-adenosylmethionine (SAM): The primary methyl donor in cellular methylation reactions, required for epigenetic modifications and methyltransferase activity.

Neddylation: A post-translational modification involving conjugation of NEDD8 to cullin proteins, regulating ubiquitin ligase activity.

SIRT3: A mitochondrial NAD+-dependent deacetylase that governs fatty acid oxidation and reactive oxygen species homeostasis.

UBC12: An E2 NEDD8-conjugating enzyme that facilitates cullin neddylation and proteasomal degradation of target proteins.

References

1. NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins. Advanced Science (2023).
2. NNMT activation can contribute to the development of fatty liver disease by modulating the NAD+ metabolism. Scientific Reports (2018).
3. Association of nicotinamide-N-methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulin resistance. Diabetologia (2015).
4. A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders. Scientific Reports (2018).
5. Complex roles of nicotinamide N-methyltransferase in cancer progression. Cell Death & Disease (2022).