GETomics based bulk-RNA sequencing revealed HIF-3α prevents COPD by inhibiting alveolar epithelial cell ferroptosis via the HIF-3α-GPx4 axis.

COPD patients are largely asymptomatic until later stages when prognosis is generally poor. Here, by shifting the focus forward to pre-COPD and smoking stages, we found the peak of reactive oxygen species (ROS) level and hypoxia character are enriched in pre-COPD samples, and hypoxia inducible factor (HIF)-3α is the key factor. Smoking induced regional tissue hypoxia and emphysema have been found in COPD patients. However, the mechanisms underlying hypoxia especially HIF-3α and COPD have not been investigated. In this study, by leveraging scRNA-seq and EpCAM co-localization analysis we identified HIF-3α is downregulated in alveolar epithelial cells in COPD. In vitro experiments using lentivirus transfection, bulk-RNA seq and RSL3 we found the activation of HIF-3α-GPx4 axis inhibits alveolar epithelial cell ferroptosis under the treatment of cigarettes smoking extracts (CSE). Further results from SftpcCreert2/+R26LSL-Hif3a knock-in mice demonstrated overexpression of HIF-3α inhibits alveolar epithelial cells ferroptosis and prevents the declining of lung function. Our data suggest the activation of HIF-3α-GPx4 axis prevents COPD by inhibiting alveolar epithelial cells ferroptosis. By leveraging this comprehensive analysis method, more promising treatment targets will be found and enhance our understanding to the pathogenesis.