NNMT as a therapeutic target in fibrosis: Insights from the heart, liver, kidneys, and lungs

Fibrosis, a key pathological process in chronic diseases, involves excessive extracellular matrix deposition that causes organ dysfunction. Due to the limitations of current therapies, identifying new treatment targets is essential. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that links NAD⁺ metabolism and epigenetic regulation by consuming nicotinamide (NAM) and S-adenosylmethionine (SAM). This review summarizes the role of NNMT in fibrosis across multiple organs. Evidence shows that NNMT is markedly upregulated in fibrotic tissues, acting as a critical metabolic driver that promotes disease progression through NAD⁺ depletion, mitochondrial dysfunction, reduced SAM/SAH ratio, fibroblast activation, and feedback loops via pathways like TGF-β1/Smad3. It also exhibits organ-specific mechanisms such as influencing hepatic stellate cells in the liver and cellular senescence in the kidneys. Given its central role in driving fibrogenesis, developing potent and selective NNMT inhibitors has emerged as an urgent therapeutic priority. Current therapeutic strategies targeting NNMT include small-molecule inhibitors, gene-based therapies, and natural compounds. Future work should focus on advancing these inhibitors toward clinical translation and understanding tissue-specific roles of NNMT and its metabolites. Targeting NNMT offers a promising approach for treating fibrosis.