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

Apr 8, 2026Differentiation; research in biological diversity

Targeting NNMT to treat scarring in the heart, liver, kidneys, and lungs

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Abstract

Nicotinamide N-methyltransferase (NNMT) is markedly upregulated in fibrotic tissues.

NNMT acts as a critical metabolic driver in fibrosis, promoting disease progression.
Elevated NNMT levels are associated with NAD depletion and mitochondrial dysfunction.
The enzyme influences fibroblast activation and creates feedback loops through pathways like TGF-β1/Smad3.
NNMT has organ-specific mechanisms, affecting hepatic stellate cells in the liver and cellular senescence in the kidneys.
Developing potent and selective NNMT inhibitors is an urgent therapeutic priority.

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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 NADmetabolism 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 NADdepletion, 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. + +

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

Abstract

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