Identification and validation of a ferroptosis-related gene to predict survival outcomes and the immune microenvironment in lung adenocarcinoma

Abstract

Abstract Background Lung adenocarcinoma (LUAD) is a leading cause of cancer-related death worldwide. Ferroptosis, a form of cell death characterized by iron-dependent lipid peroxidation. However, the involvement of ferroptosis in the regulation of immune cell infiltration and its immunotherapeutic efficacy in LUAD remain unclear. Methods The Cancer Genome Atlas (TCGA) LUAD cohort was used to assess the survival prognosis of FRGs and construct a seven-gene risk signature. Correlation tests, difference tests, and a cluster analysis were performed to explore the role of FRGs in the immune microenvironment and their immunotherapeutic efficacy in LUAD. The effects of FRGs on LUAD cells were assessed by Western blot, iron assay, and lipid peroxidation assay. Results The seven-gene risk signatures of patients with LUAD were established and validated. FRG clustering based on 70 differentially expressed FRGs was associated with the immune microenvironment and indicated potential immune subtypes of LUAD. The seven-gene risk signature was an independent prognostic factor for LUAD and was used to divide the LUAD cohort into a high-risk and a low-risk group. Immunocyte infiltration levels, immune checkpoints, and immunotherapy response rates were significantly different between the two groups. Patients with high risk scores had lower overall levels of immunocyte infiltration but higher immunotherapy response rates. The key gene ribonucleotide reductase subunit M2 (RRM2) was associated with LUAD prognosis, which may be related to its ability to regulate the infiltration levels of activated mast cells and activated CD4 memory T cells. In addition, RRM2 was involved in ferroptosis, and its expression was up regulated in lung cancer tissues and the LUAD cell lines. Silencing RRM2 can inhibit the proliferation and induce ferroptosis of H1975 cells suggesting that silencing RRM2 could promote ferroptosis in H1975 cells. Conclusion Our results revealed RRM2 as a promising biomarker and therapeutic target associated with tumor immune infiltration in patients with LUAD.