Nicotinamide N-methyltransferase (NNMT) is a crucial enzyme that catalyzes the methylation of nicotinamide using S-adenosyl-L-methionine as the methyl donor. This reaction connects one-carbon metabolism mediated by methylation with nicotinamide adenine dinucleotide levels. NNMT is involved in multiple cellular metabolic pathways and has been linked to various physiological and pathological conditions [4].

NNMT has been found to be highly relevant in several disease contexts. In high-grade serous carcinoma, stromal NNMT expression is necessary for the cancer-associated fibroblast (CAF) phenotype, supporting ovarian cancer migration, proliferation, and metastasis [1]. In triple-negative breast cancer, NNMT overexpression promotes metastasis by enhancing the PP2A/MEK/ERK/c-Jun/ABCA1 pathway-mediated membrane fluidity [2]. Also, in early gastric cardia adenocarcinoma, NNMT enriches for AQP5 + cancer stem cells to drive malignant progression [5]. In breast cancer, NNMT/1-MNA promote cell-cycle progression by targeting UBC12/Cullin-1-mediated degradation of P27 proteins [6]. Moreover, in alcohol-related fatty liver development, ER stress-induced upregulation of NNMT contributes to the pathogenesis, and its inhibition protects against fatty liver development [3].

In conclusion, NNMT is a key enzyme in various biological processes and diseases. Studies, including those using potential gene-knockout or conditional-knockout mouse models (implied by in vivo studies), have revealed its significance in cancer progression, liver disease development, and other conditions. Understanding NNMT's functions provides potential therapeutic targets for treating related diseases.