Hrh4, the histamine H4 receptor gene, is a key component in the histamine receptor family. Histamine, acting through its receptors, is involved in multiple physiological and pathological processes. HRH4 has been shown to play roles in inflammation, cell growth regulation, and immune cell function. It is expressed in various tissues including neurons, vascular endothelial cells, eosinophils, and cells of the gastrointestinal tract [3,4,5,7,8].

In non-small cell lung cancer (NSCLC), the rs11662595 mutation in HRH4 decreases its ability to activate Gi protein, facilitating epithelial-to-mesenchymal transition (EMT), cell proliferation, and invasion. This mutation also attenuates the anti-EMT effects of HRH4 agonist in vivo [1]. In ankylosing spondylitis, certain HRH4 polymorphisms (rs657132 AA genotype and A-A haplotype in rs8088140-rs657132) are associated with increased disease susceptibility [2]. In colorectal and gastric carcinomas, the expression of HRH4 is reduced, which may influence histamine-mediated growth regulation of cancer cells [4,7]. In addition, in Leydig cells, activation of HRH4 inhibits steroidogenesis and cell proliferation [8]. In age-related macular degeneration and diabetic retinopathy, HRH4 antagonists show potential as therapeutic agents as they can reduce choroidal neovascularization and prevent macrophage infiltration and retinal vascular leakage respectively, without causing retinal toxicity [5,6].

In conclusion, HRH4 is involved in diverse biological processes, especially in inflammation and cell growth-related pathways. Genetic models, though not specifically KO/CKO mouse models in these references, have helped identify its role in diseases such as NSCLC, ankylosing spondylitis, colorectal and gastric carcinomas, age-related macular degeneration, and diabetic retinopathy. Understanding HRH4 function provides potential therapeutic targets for these diseases.