Aldh1a3, an enzyme in the aldehyde dehydrogenase family, is crucial for oxidizing all-trans-retinal to retinoic acid, participating in various physiological processes. It has been associated with multiple pathways such as glycometabolism, and is linked to important biological functions like cell proliferation, metabolism regulation, and in disease contexts, cancer development and chemoresistance [3,4]. Genetic models, including KO/CKO mouse models, are valuable for studying its functions.

In pulmonary arterial hypertension (PAH), Aldh1a3 is highly upregulated in pulmonary arterial smooth muscle cells (PASMC) from PAH patients. Mice with Aldh1a3 deleted in SMC did not develop hypoxia-induced pulmonary arterial muscularization or pulmonary hypertension. Nuclear Aldh1a3 converts acetaldehyde to acetate, which leads to histone acetylation and subsequent regulation of genes related to cell cycle and metabolism, highlighting its role in coordinating metabolism and gene regulation in PAH [2]. In glioblastoma, Aldh1a3-overexpressing patients show limited benefit from chemoradiotherapy. Aldh1a3 interacts with PKM2, promoting its tetramerization and lactate accumulation. Disrupting this interaction with D34-919 enhances chemoradiotherapy-induced apoptosis of glioblastoma cells [1].

In conclusion, Aldh1a3 plays essential roles in coordinating metabolism and gene regulation, as well as influencing cancer-related processes like chemoresistance. The use of Aldh1a3 KO/CKO mouse models has provided valuable insights into its functions in diseases such as PAH and glioblastoma, helping us understand the underlying mechanisms and potentially guiding the development of new therapeutic strategies.