ALAS2, also known as 5-aminolevulinate synthase 2, is a key enzyme in the heme biosynthetic pathway, specifically in erythroid cells. It catalyzes the rate-controlling step of erythroid heme synthesis. Heme is essential for various biological functions such as oxygen transport, electron transfer, and enzyme catalysis. Mutations in ALAS2 can lead to disorders related to abnormal heme production, highlighting its biological importance. Genetic models, like gene-knockout (KO) models, can be valuable for studying its function [2,3,4].

In aortic aneurysm studies, ALAS2 overexpression alleviated oxidative stress-induced ferroptosis via GATA1 activation. Hydrogen peroxide-treated mouse aortic vascular smooth muscle cells showed increased iron content and oxidative stress, with upregulated ALAS2 protein levels. Overexpressing ALAS2 reversed H2O2-induced apoptosis and inflammatory cytokine level changes. Knocking down GATA1 partially reversed the protective effect of overexpressed ALAS2 on ferroptosis, suggesting potential therapeutic targets in aortic aneurysms [1]. In X-linked protoporphyria, gain-of-function mutations in ALAS2 lead to the disease. ALAS2 gain-of-function mutants had increased enzyme activity and altered thermostability [3]. In congenital sideroblastic anemia, mutations in ALAS2 cause defective heme biosynthesis, leading to ring sideroblast formation and increased susceptibility to ferroptosis, as seen in XLSA clones with missense mutations [5].

In conclusion, ALAS2 is crucial for erythroid heme synthesis. Model-based research, especially in diseases like aortic aneurysm, X-linked protoporphyria, and congenital sideroblastic anemia, has revealed its role in oxidative stress, ferroptosis, and heme-related disorders. Understanding ALAS2 function through these models provides insights into potential therapeutic strategies for these diseases.