Nicotinamide N-methyltransferase (NNMT) is a crucial enzyme that catalyzes nicotinamide methylation using S-adenosyl-L-methionine as the methyl donor. This reaction links one-carbon metabolism with nicotinamide adenine dinucleotide levels, playing a pivotal role in maintaining cellular homeostasis [4]. NNMT is involved in multiple metabolic pathways and has been associated with various biological processes and diseases.

In the context of alcohol-related liver disease (ALD), chronic alcohol consumption induces endoplasmic reticulum (ER) stress, which upregulates NNMT expression in the liver via the PERK-ATF4 pathway. In liver-specific Atf4 knockout mice, alcohol fails to upregulate NNMT. Inhibiting NNMT, either genetically or pharmacologically, prevents fatty liver development in response to chronic alcohol feeding, associated with downregulation of de novo lipogenesis genes and enhanced liver AMPK activation [1]. In cancer, studies on cell lines and mouse tumor xenografts show that NNMT expression negatively correlates with cancer cell sensitivity to oxidative phosphorylation (OXPHOS) inhibition. NNMT overexpression renders OXPHOS-inhibition-sensitive cancer cells resistant [2]. In triple-negative breast cancer (TNBC), NNMT overexpression promotes migration and invasion in vitro by reducing cholesterol levels and enhancing membrane fluidity through the PP2A/MEK/ERK/c-Jun/ABCA1 pathway. Targeting NNMT weakens the metastasis capacity of TNBCs in vivo [3].

In summary, NNMT is a key enzyme in multiple biological processes. Its role in diseases such as ALD and cancer has been revealed through gene-knockout models and other functional studies. In ALD, NNMT is involved in fatty liver development, and in cancer, it affects cell sensitivity to OXPHOS inhibition and metastasis. These findings suggest that NNMT could be a potential therapeutic target for these diseases.

References:

1. Song, Qing, Chen, Yingli, Wang, Jun, Zhou, Zhangxiang, Song, Zhenyuan. 2020. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development. In Journal of hepatology, 73, 783-793. doi:10.1016/j.jhep.2020.04.038. https://pubmed.ncbi.nlm.nih.gov/32389809/

2. Wu, Changqing, Liu, Yu'e, Liu, Wenju, Jiang, Cizhong, Shi, Yufeng. 2022. NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2202642. doi:10.1002/advs.202202642. https://pubmed.ncbi.nlm.nih.gov/36382559/

3. Wang, Yanzhong, Zhou, Xi, Lei, Yinjiao, Xie, Xinyou, Zhang, Jun. 2022. NNMT contributes to high metastasis of triple negative breast cancer by enhancing PP2A/MEK/ERK/c-Jun/ABCA1 pathway mediated membrane fluidity. In Cancer letters, 547, 215884. doi:10.1016/j.canlet.2022.215884. https://pubmed.ncbi.nlm.nih.gov/35988817/

4. Park, Jeongwoo, Shin, Eun Jin, Kim, Tae Hyun, Kang, Keon Wook, Kim, Kyu Min. 2024. Exploring NNMT: from metabolic pathways to therapeutic targets. In Archives of pharmacal research, 47, 893-913. doi:10.1007/s12272-024-01519-9. https://pubmed.ncbi.nlm.nih.gov/39604638/