Screening for Potential Therapeutic Agents for Non-Small Cell Lung Cancer by Targeting Ferroptosis

Ferroptosis is a form of non-apoptotic and iron-dependent cell death originally identified in cancer cells. Recently, emerging evidence showed that ferroptosis-targeting therapy could be a novel promising anti-tumour treatment. However, systematic analyses of ferroptosis-related genes for the prognosis of non-small cell lung cancer (NSCLC) and the development of antitumor drugs exploiting the ferroptosis process remain rare. This study aimed to identify genes related to ferroptosis and NSCLC and to initially screen lead compounds that induce ferroptosis in tumor cells. We downloaded mRNA expression profiles and NSCLC clinical data from The Cancer Genome Atlas database to explore the prognostic role of ferroptosis-related genes. Four prognosis-associated ferroptosis-related genes were screened using univariate Cox regression analysis and the lasso Cox regression analysis, which could divide patients with NSCLC into high- and low-risk groups. Then, based on differentially expressed risk- and ferroptosis-related genes, the negatively correlated lead compound flufenamic acid (FFA) was screened through the Connective Map database. This project confirmed that FFA induced ferroptosis in A549 cells and inhibited growth and migration in a dose-dependent manner through CCK-8, scratch, and immunofluorescence assays. In conclusion, targeting ferroptosis might be a therapeutic alternative for NSCLC.