Transcriptomic analysis and validation study of key genes and the HIF‑1α/HO‑1 pathway associated with ferroptosis in neutrophilic asthma

Ferroptosis, as a unique form of cell death caused by iron overload and lipid peroxidation, is involved in the pathogenesis of various inflammatory diseases of the airways. Inhibition of ferroptosis has become a novel strategy for reducing airway epithelial cell death and improving airway inflammation. The aim of the present study was to analyze and validate the key genes and signaling pathways associated with ferroptosis by bioinformatic methods combined with experimental analyzes <i>in vitro</i> and <i>in vivo</i> to aid the diagnosis and treatment of neutrophilic asthma. A total of 1,639 differentially expressed genes (DEGs) were identified in the transcriptome dataset. After overlapping with ferroptosis-related genes, 11 differentially expressed ferroptosis-related genes (DE-FRGs) were obtained. A new diagnostic model was constructed by these DE-FRGs from the transcriptome dataset with those from the GSE108417 dataset. The receiver operating characteristic curve analysis indicated that the area under the curve had good diagnostic performance (>0.8). As a result, four key DE-FRGs (CXCL2, HMOX1, IL-6 and SLC7A5) and biological pathway [hypoxia-inducible factor 1 (HIF-1) signaling pathway] associated with ferroptosis in neutrophilic asthma were identified by the bioinformatics analysis combined with experimental validation. The upstream regulatory network of key DE-FRGs and target drugs were predicted and the molecular docking results from screened 37 potential therapeutic drugs revealed that the 13 small-molecule drugs exhibited a higher stable binding to the primary proteins of key DE-FRGs. The results suggested that four key DE-FRGs and the HIF-1α/heme oxygenase 1 pathway associated with ferroptosis have potential as novel markers or targets for the diagnosis or treatment of neutrophilic asthma.