Hnmt, or histamine N-methyltransferase, is an enzyme crucial for histamine metabolism. Histamine is a mediator in allergic responses, regulator of gastric acid secretion, messenger in bronchial asthma, and neurotransmitter in the central nervous system. Hnmt terminates histamine's local action primarily by methylation [2]. It has a 2-domain structure with a consensus AdoMet binding domain, and a common polymorphism at residue 105 (Thr/Ile) correlates with high-and low-activity phenotypes [2].

In non-small-cell lung cancer (NSCLC), Hnmt is significantly upregulated, co-expressed with HER2, and its upregulation may increase tumorigenicity and chemoresistance through cancer stem cell maintenance and antioxidant properties. Depletion of Hnmt in NSCLC cells decreased cell proliferation, colony formation, etc. [1].

In the enteric nervous system, glial Hnmt contributes to histamine clearance, and its deletion in male mice, but not females, affects visceromotor responses and protects males from histamine-driven visceral hypersensitivity [3].

In the brain, Hnmt-deficient mice show a robust increase in brain histamine concentration, and human Hnmt gene single-nucleotide polymorphisms are associated with brain disorders like Parkinson's disease [4]. A meta-analysis also indicates that the minor allele of the Hnmt rs11558538 SNP is related to a reduced risk of developing Parkinson's disease [5].

In conclusion, Hnmt plays essential roles in histamine metabolism across various biological systems. Gene knockout models in mice, such as Hnmt-deficient mice, have been instrumental in revealing its functions in diseases including NSCLC, visceral hypersensitivity, and brain disorders like Parkinson's disease. These models help in understanding the mechanisms underlying these diseases and potentially developing new therapeutic strategies.