Nicotinamide N-methyltransferase in inflammatory bowel disease: Multidimensional regulation, mechanistic insights, and therapeutic potential.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder involving immune, metabolic, microbial, and epigenetic dysregulation. Nicotinamide N-methyltransferase (NNMT) connects nicotinamide metabolism with NAD+ availability, methyl-donor homeostasis, and epigenetic regulation. Accumulating evidence shows that NNMT is upregulated in intestinal tissues from patients with IBD and may promote disease progression by reducing nicotinamide adenine dinucleotide (NAD+) availability, increasing homocysteine (Hcy) accumulation, and disturbing DNA and histone methylation. These changes may contribute to mitochondrial dysfunction, epithelial barrier impairment, gut microbiota dysbiosis, and enteric nervous system disturbance. This review summarizes current evidence on the role of NNMT in IBD and discusses emerging NNMT-targeted strategies, including small-molecule inhibitors, RNA-based silencing approaches, and exercise-based interventions. Collectively, NNMT represents a metabolic-epigenetic hub in IBD pathogenesis and a promising target for future therapeutic development.