Chrna5, encoding the α5 subunit of the nicotinic acetylcholine receptor (nAChR), is a key gene involved in the cholinergic system. nAChRs are ligand-gated ion channels, and the α5 subunit is part of the CHRNA5-CHRNA3-CHRNB4 gene cluster. This gene cluster is associated with smoking heaviness, nicotine dependence, and the response to drugs of abuse [2,3].

Genetic variation in CHRNA5, such as the rs16969968 polymorphism, is associated with an increased risk of lung cancer in European populations, and the minor allele A may increase the risk in both smokers and non-smokers [1]. The rs16969968 allele (A) is also associated with a lower likelihood of smoking cessation and an earlier age of lung cancer diagnosis in Europeans [4]. In hepatocellular carcinoma, CHRNA5 expression is increased, and it promotes tumor progression by regulating YAP activity, stemness-associated genes, and epithelial-mesenchymal transition-associated genes, and also affects sorafenib sensitivity [5]. In psoriasis, CHRNA5 is highly expressed in lesional skin, and its knockout in mice reduces psoriasis severity and regulates inflammation through the MAPK kinase kinase-1/c-Jun N-terminal kinase‒MAPK/NF-κB pathway [6]. In head and neck squamous cell carcinoma, nicotine-induced CHRNA5 activation modulates CES1 expression via the MEK/ERK pathway, contributing to recurrence and metastasis [7].

In conclusion, Chrna5 is crucial in the cholinergic system and is associated with multiple diseases, especially those related to smoking. Mouse models, such as gene-knockout models, have provided insights into its role in disease development, including its impact on cancer progression and inflammation-related diseases, highlighting its potential as a therapeutic target.