Chrna4, encoding the α4 subunit of nicotinic acetylcholine receptors (nAChRs), is crucial for controlling neurotransmitter release and is involved in multiple physiological and pathological processes. It has been associated with pathways related to cognitive function, nicotine addiction, and inflammation [1,2,3,4]. Genetic models, like knockout mouse models, have been instrumental in studying its functions [5].

In metabolic dysfunction-associated steatohepatitis (MASH), Chrna4 is expressed in hepatocytes and its levels increase in mice and patients with MASH, positively correlating with disease severity. Immune-cell-released acetylcholine or smoking-derived nicotine activates hepatocyte-intrinsic Chrna4, leading to calcium influx, inflammatory signaling, and cytokine production, promoting MASH pathogenesis. Genetic and pharmacological inhibition of Chrna4 protects mice from diet-induced MASH [1]. In nicotine-related studies, Chrna4 A529 knock-in mice show altered nicotine sensitivity, including greater sensitivity to nicotine's hypothermic effects, reduced oral nicotine consumption, and no development of conditioned place preference to nicotine [5].

In conclusion, Chrna4 is essential for normal physiological functions related to neurotransmission and is implicated in diseases such as MASH and nicotine-related disorders. The use of gene-knockout mouse models has significantly enhanced our understanding of Chrna4's role in these disease areas, highlighting its potential as a therapeutic target for MASH and a factor influencing nicotine-related behaviors.