Nicotinamide N-methyltransferase as a stress-responsive metabolic-epigenetic regulator of tubular senescence in chronic kidney disease

Chronic kidney disease (CKD) is characterized by persistent cellular stress, tubular dysfunction, and progressive tubulointerstitial fibrosis. Increasing evidence suggests that senescence of renal tubular epithelial cells (RTECs) represents an important pathological process linking chronic injury to fibrotic remodeling. Nicotinamide N-methyltransferase (NNMT), a metabolic enzyme involved in nicotinamide methylation, has recently attracted attention because of its potential role in stress-associated metabolic and epigenetic regulation. In this review, we summarize current evidence regarding stress-responsive regulation of NNMT and discuss its potential involvement in tubular senescence during CKD progression. Available studies suggest that NNMT expression can be dynamically altered under various stress conditions, though the direction of change varies with cell type and context. Through consumption of nicotinamide and S-adenosylmethionine, sustained NNMT activation may influence nicotinamide adenine dinucleotide (NAD⁺) homeostasis, methyl donor balance, and homocysteine metabolism, thereby affecting redox regulation, epigenetic remodeling, and senescence-associated signaling pathways. We further discuss the potential interactions between NNMT-associated metabolic dysregulation, chronic stress responses, tubular senescence, and fibrosis. Current evidence, though largely correlative, suggests that NNMT may represent a stress-associated metabolic regulator and a potential therapeutic target in CKD.