Abstract / Summary
Lung adenocarcinoma (LUAD) is the largest subtype of lung cancer. Ferroptosis resistance is an important mechanism for tumor growth, but the complete mechanism map in LUAD needs further improvement. FerrDb-derived drivers, suppressors and markers were screened through differential expression analysis and weighted gene co-expression network analysis (WGCNA) in the GSE140797 dataset. A prognostic signature was then established in the TCGA-LUAD cohort using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression, and externally validated in the GSE50081 cohort. The GSE131907 dataset was used for single-cell RNA sequencing (scRNA-seq) analysis to reveal the expression characteristics and biological effects of key genes. Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and Western blot (WB) assays were used to verify the biological effects and potential mechanisms of key genes. Ferroptosis-related genes (FRGs) related to LUAD occurrence were screened out through differential expression analysis and WGCNA. A prognostic signature consisting of six FRGs was verified via LASSO regression and multivariate analyses. Among them, very low density lipoprotein receptor (VLDLR) was an important risk gene, and its expression was significantly correlated with tumor microenvironment (TME) remodeling, mutation heterogeneity and differences in therapeutic response in LUAD. The VLDLR-positive LUAD epithelial cell subset had low differentiation potential and was associated with focal adhesion. In vitro experiments showed that VLDLR-II was mainly highly expressed in LUAD tissues, and LUAD cells with high VLDLR-II expression had increased proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) abilities, which was related to the activation of the FAK/Src pathway. The prognostic model based on six FRGs shows predictive ability and clinical applicability. VLDLR is an independent risk factor for predicting LUAD patients, and the upregulated expression of its type II subtype promotes tumor cell growth and EMT by activating the FAK/Src pathway.