The emerging role of nicotinamide N-methyltransferase in the pathogenesis and treatment of breast cancer.

Nicotinamide N-methyltransferase (NNMT) plays a critical role in the pathogenesis, progression, and treatment resistance of breast cancer (BC). This enzyme facilitates tumor progression through multiple mechanisms: it regulates NAD metabolism, thereby influencing the activity of key enzymes such as sirtuins (SIRTs) and Poly(ADP-ribose) polymerase (PARP), which drives metabolic reprogramming and enhances chemoresistance; it consumes the methyl donor S-adenosylmethionine (SAM), leading to histone hypomethylation and promoting the expression of genes associated with epithelial-mesenchymal transition (EMT) and metastasis; and its metabolite, 1-methylnicotinamide (MNA), acts as a signaling molecule within the tumor microenvironment (TME) to accelerate tumor development by facilitating cell cycle progression and suppressing protective autophagy. NNMT is frequently overexpressed in BC tissues and is correlated with poor prognosis, highlighting its potential as a diagnostic biomarker and therapeutic target. Studies have demonstrated that targeting NNMT effectively inhibits tumor growth and metastasis and may augment the efficacy of immunotherapy. Future research should prioritize the development of potent NNMT inhibitors and further elucidate the role of NNMT in modulating the TME and mediating drug resistance. As a pivotal molecule linking metabolism, epigenetics, and the TME, NNMT offers promising new avenues for BC treatment.