Nicotinamide N-methyltransferase as a potential therapeutic target for neurodegenerative disorders: Mechanisms, challenges, and future directions.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss and functional decline, posing significant global health challenges. Emerging evidence highlights nicotinamide N-methyltransferase (NNMT), a cytosolic enzyme regulating nicotinamide (NAM) methylation, as a pivotal player in NDs through its dual impact on epigenetic regulation and metabolic homeostasis. This review synthesizes current knowledge on NNMT's role in disease pathogenesis, focusing on its epigenetic modulation via DNA hypomethylation and histone modifications, alongside its disruption of NAD synthesis and homocysteine (Hcy) metabolism. Elevated NNMT activity depletes NAD, exacerbating mitochondrial dysfunction and impairing energy metabolism, while increased Hcy levels drive oxidative stress, neuroinflammation, and aberrant protein aggregation (e.g., Aβ, tau, α-synuclein). Notably, NNMT overexpression in AD and PD correlates with neuronal hypomethylation and neurotoxicity, as observed in postmortem brain studies and transgenic models. Mechanistically, NNMT consumes S-adenosylmethionine (SAM), limiting methyl donor availability for DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), thereby altering gene expression patterns critical for neuronal survival. Concurrently, NNMT-mediated NAD depletion disrupts sirtuin activity (e.g., SIRT1) and mitochondrial biogenesis, accelerating axonal degeneration. Therapeutic strategies targeting NNMT, such as RNA interference (RNAi), small-molecule inhibitors and exercise therapy, show promise in preclinical models by restoring NAD levels and reducing Hcy toxicity. However, challenges persist in achieving cellular specificity, optimizing blood-brain barrier penetration, and mitigating off-target effects. This review underscores NNMT's potential as a multifactorial therapeutic target, bridging metabolic and epigenetic dysregulation in NDs. Future research should prioritize elucidating tissue-specific NNMT interactions, refining inhibitor pharmacokinetics, and validating translational efficacy in clinical trials. Addressing these gaps could pave the way for novel disease-modifying therapies to combat the rising burden of neurodegeneration.