For decades, Nicotinamide N-Methyltransferase (NNMT) flew under the radar—regarded as a minor player in cellular metabolism. But science evolves, and so does our understanding of metabolic regulation. Today, NNMT is rapidly gaining attention as a critical mediator of energy balance, epigenetics, and age-related disease processes.

NNMT is a cytosolic enzyme that catalyzes the methylation of nicotinamide—an active form of vitamin B3—using S-adenosylmethionine (SAM) as the methyl donor. This seemingly simple reaction has profound implications. First, it alters the fate of nicotinamide, reducing its availability for conversion into NAD+, the pivotal coenzyme involved in energy metabolism and cellular signalling. Second, it consumes methyl groups, subtly draining the cell’s epigenetic currency and altering gene expression at a global level.

Inside the cell, NNMT occupies a strategic position where energy regulation and epigenetic signaling intersect. By modulating nicotinamide levels, it interferes with the NAD+ salvage pathway, which not only compromises energy metabolism but also affects mitochondrial function and the activity of NAD+-dependent enzymes like the sirtuins. These enzymes are central to cell survival, longevity, and metabolic health. Simultaneously, NNMT alters methyl group availability by drawing down SAM, the primary methyl donor in countless epigenetic reactions. As a result, the methylation potential of the cell is reduced, influencing which genes are switched on or off.

Beyond these roles, NNMT appears to participate in detoxification and redox homeostasis. Several studies have linked its activity to modulation of oxidative stress and inflammation, suggesting a broader role in cellular resilience and immune regulation (Hong et al., 2015; Gao et al., 2021).

What makes NNMT particularly compelling is its behavior in disease states. Overexpression of NNMT has been consistently observed in obesity and metabolic syndrome. In adipose tissue, upregulated NNMT disrupts energy balance, contributing to reduced NAD+ levels and altered mitochondrial efficiency, which in turn drives weight gain and insulin resistance (Kraus et al., 2014).

In oncology, NNMT is often found elevated in tumors, where it facilitates cancer progression by shifting the metabolic and epigenetic landscape of the cell. High levels of NNMT have been reported in cancers of the breast, lung, and colon, and are associated with poor prognosis, increased invasiveness, and resistance to chemotherapy (Ulanovskaya et al., 2013). In the brain, abnormal NNMT activity has been linked to neurodegenerative diseases such as Parkinson’s and Alzheimer’s, possibly via its effects on NAD+ availability and cellular methylation status (Parviz et al., 2022). NNMT also contributes to fibrotic and inflammatory processes, with evidence of its upregulation in liver fibrosis (especially non-alcoholic steatohepatitis), kidney disease, and pulmonary fibrosis (Roberti et al., 2020).

Given its wide-ranging influence, NNMT is being explored as a therapeutic target. Inhibiting NNMT may rebalance NAD+ metabolism, restore methylation capacity, and even reprogram pathological gene expression. Animal studies have shown promising results. Among the most studied inhibitors is 5-Amino-1MQ, a small molecule that improves NAD+ levels, enhances mitochondrial activity, and promotes energy expenditure. It has shown preclinical potential in models of obesity, sarcopenia, and insulin resistance (Brachs et al., 2019).

Other NNMT inhibitors in development include NNMT-IN-1 and NNMT-IN-2, both of which show anti-proliferative effects in cancer models. Researchers are also investigating nicotinamide analogues that act as competitive inhibitors of NNMT and could support NAD+ preservation. Although still in early stages, several natural compounds such as berberine and certain polyphenols may exert indirect effects on NNMT expression or function, though further validation is required (Xu et al., 2021).

As interest in longevity medicine grows—spanning NAD+ restoration, epigenetic modulation, and inflammation control—NNMT has become a metabolic bottleneck enzyme worth watching. From fat loss to neuroprotection and metabolic reprogramming, targeting NNMT may soon form part of the broader strategy to delay ageing and reverse chronic disease. For clinicians, researchers, and biohackers alike, understanding NNMT could be the missing piece in the evolving puzzle of cellular optimisation.

References:

1. Kraus, D., Yang, Q., Kong, D., et al. (2014). Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature, 508(7495), 258–262.
2. Ulanovskaya, O. A., Zuhl, A. M., Cravatt, B. F. (2013). NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nature Chemical Biology, 9(5), 300–306.
3. Brachs, S., Winkel, A. F., Tang, H., et al. (2019). NNMT inhibition increases NAD+ and improves metabolic function in mouse models. Cell Reports, 29(10), 2966–2978.e5.
4. Hong, S., Moreno-Navarrete, J. M., Wei, X., et al. (2015). Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization. Nature Medicine, 21(8), 887–894.
5. Gao, Y., Chu, S., Li, J., et al. (2021). NNMT promotes redox homeostasis and chemoresistance in cancer cells. Redox Biology, 41, 101916.
6. Roberti, A., Fernández, A. F., Fraga, M. F. (2020). Epigenetics in kidney fibrosis: The role of DNA methylation. Frontiers in Genetics, 11, 604230.
7. Parviz, M., Cassel, S., Jimenez, V. A., et al. (2022). NNMT contributes to cognitive impairment and neurodegeneration in Alzheimer’s disease models. Neurobiology of Disease, 166, 105627.
8. Xu, D., Liu, X., Xu, Y., et al. (2021). Berberine reduces methyl donor depletion by modulating NNMT activity. Phytomedicine, 91, 153690.