Abstract
BACKGROUND: Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been implicated in the pathogenesis of asthma. This study aimed to identify and validate ferroptosis-related genes (FRGs) associated with asthma through bioinformatics analysis, clinical samples, and experimental validation, thus providing new insights for treatment. METHODS: Transcriptome data from induced sputum samples of asthma patients were obtained from the GEO database. Differentially expressed genes (DEGs) were subjected to GO and KEGG enrichment analyses. In addition, LASSO and SVM-RFE algorithms were employed to screen FRGs related to asthma. The expression levels and predictive efficacy of the signature genes were verified by differential expression analysis and ROC curves, and ssGSEA was used to further analyze their relationship with immune cell infiltration levels. Lung tissue samples from clinical cases were collected to validate gene expression in vivo. Additionally, BEAS-2B cells were selected for in vitro experiments, and small interfering RNA silencing and pcDNA3.1 overexpression candidate genes were used to further validate their role in ferroptosis. RESULTS: The FRGs TFRC and CRYAB were identified as differentially expressed in asthma. Immune infiltration analysis revealed significant alterations in immune cell abundance that correlated with signature gene expression levels in asthmatic samples. However, only CRYAB was significantly upregulated in lung tissues from asthmatic patients compared to controls. In vitro experiments demonstrated that erastin-induced ferroptosis led to downregulation of CRYAB expression in BEAS-2B cells; conversely, overexpression of CRYAB resulted in decreased MDA and ROS levels but increased GSH content, thereby protecting BEAS-2B cells against ferroptosis. CONCLUSION: This study is the first to highlight the pivotal role of CRYAB among FRGs in asthma pathogenesis. Notably, overexpression of CRYAB inhibits ferroptosis-suggesting its potential as a valuable biomarker for personalized diagnosis and therapy for asthma.