Epas1, also known as HIF2A, is a transcription factor that serves as a master regulator of the adaptive response to hypoxia. It forms a heterodimer with the ARNT/HIF-1β subunit and is involved in various cellular processes. Central to its function is its role in oxygen (O2) homeostasis, which impacts diverse biological processes and disease states [2].

In the context of diseases, inducible endothelial Epas1 deletion in mice increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function of endothelial Epas1. It attenuates atherosclerosis initiation at disturbed flow sites by maintaining endothelial proliferation via fatty acid uptake and metabolism [1]. In chronic mountain sickness (CMS), EPAS1 might participate in the pathogenesis of excessive erythrocytosis by regulating the proliferation of erythroblasts, as EPAS1 expression in bone marrow erythroblasts was higher in CMS patients, and its variation was correlated with RBC levels and SaO2 [3]. In clear cell renal cell carcinoma, atractylenolide I inhibits angiogenesis and reverses sunitinib resistance through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α [4].

In conclusion, Epas1 plays essential roles in oxygen homeostasis and various disease-related biological processes. Studies using gene-knockout models, such as inducible endothelial Epas1 deletion in mice, have revealed its atheroprotective function. In diseases like CMS and clear cell renal cell carcinoma, Epas1 is implicated in disease pathogenesis and potential treatment strategies, highlighting the importance of Epas1-related research for understanding disease mechanisms and developing therapies.