Abstract
BACKGROUND: Ferroptosis is associated with cancer initiation and progression. However, the molecular mechanism and prognostic value of ferroptosis-related genes in lung squamous cell carcinoma (LUSC) are poorly understood. METHODS: The mRNA expression profiles, methylation data, and clinical information of patients with LUSC were downloaded from TCGA and GEO database. Ferroptosis-related differentially expressed genes (DEGs) were identified between cancerous and non-cancerous tissues, and their prognostic value was systemically investigated by bioinformatic analyses. RESULTS: A ferroptosis-related gene signature (ALOX5, TFRC, PHKG2, FADS2, NOX1) was constructed using multivariate Cox regression analysis and represented as a risk score. Overall survival (OS) probability was significantly lower in the high-risk group than in the low-risk group (P<0.001), and receiver operating characteristic curve showed a good predictive capacity (AUC = 0.739). The risk score was an independent prognostic factor for LUSC. A nomogram was constructed to predict the OS probabilities at 1, 3, and 5 years. High-risk score was associated with increased immune infiltration, lower methylation levels, higher immune checkpoint genes expression levels, and better chemotherapy response. Cell adhesion molecules, focal adhesion, and extracellular matrix receptor interaction were the main pathways in the high-risk group. The signature was validated using the TCGA test cohort, entire TCGA cohort, GSE30219, GSE157010, GSE73403, and GSE4573 datasets. The gene disorders in patients with LUSC were validated using real-time PCR and single-cell RNA sequencing analysis. CONCLUSIONS: A ferroptosis-related gene signature was constructed to predict OS probability in LUSC. This could facilitate novel therapeutic methods and guide individualized therapy.