Aldh2, short for aldehyde dehydrogenase 2, is a non-cytochrome P450 mitochondrial aldehyde oxidizing enzyme. Its key function is to oxidize acetaldehyde, a metabolite from alcohol drinking, into acetate. This process is crucial in alcohol metabolism and also impacts the metabolism of other endogenous and exogenous aldehydes, especially under oxidative stress [2].

In mouse models, Aldh2-deficient mice show increased lipid accumulation in the liver, which can be reversed by further Aldh2 depletion, indicating its role in alcohol-induced fatty liver regulation [1]. Aldh2-/-mice and Aldh2rs671 gene knock-in mice exhibit pulmonary and circulating NETosis in sepsis models, suggesting its importance in septic ARDS [3]. In aortic aneurysm/dissection (AAD) models, inhibition of Aldh2 retards AAD development by suppressing vascular smooth muscle cell (VSMC) phenotypical switch [4]. Aldh2-deficient mice are more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development, as they produce harmful oxidized mitochondrial DNA-enriched extracellular vesicles that activate oncogenic pathways in HCC cells [5]. Aldh2-knockout mice are more sensitive to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury through the gut-liver axis [6]. Transplanting bone marrow from APOE-/-ALDH2-/-to APOE-/-mice increases atherosclerosis plaques due to defective macrophage efferocytosis [7].

In conclusion, Aldh2 plays essential roles in multiple biological processes related to alcohol metabolism, inflammation, and disease development. Gene knockout and knock-in mouse models have significantly contributed to understanding its functions in diseases such as alcoholic fatty liver, septic ARDS, AAD, liver cancer, alcohol-associated gut and liver injury, and atherosclerosis.