Identification and Prognostic Analysis of Ferroptosis-related Genes to Predict The Progression of Lung Squamous Cell Carcinoma

Abstract Background: Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of cancer. However, the role of ferroptosis-related gene profiles in LSCCremains largely unknown. This study aims to identify the prognostic roles of ferroptosis-related genes in LSCC. Methods: We analyzed sequencing data from the Cancer Genome Atlas and identified ferroptosis-related gene expressionbetween tumors and para‐tumors. We also assessed the prognostic role of these genes using Kaplan–Meier analysis and univariable and multivariable Cox proportional hazards regression model analyses. Immunological correlation, tumor stemness, and drug sensitivity and the transcriptional differences of HSPA5 were also analyzed in LSCC. Then, we investigated the expression of HSPA5 usingimmunohistochemistry in 100 patients with metastatic LSCC and assessed the clinical significance of these markers with different risk factors. Results: Of the 22 ferroptosis-related genes, the expression of HSPA5, HSPB1, GPX4, FANCD2, CISD1, FDFT1, NFE2L2, SLC1A5, RPL8, NCOA4, TFRC, and SLC7A11 was significantly increased in LSCC compared to adjacent tissues. However, only high expression of HSPA5 can predict progression-free survival (PFS) and disease-free survival time (DFS) in LSCC. Although HSPA5 was also significantly elevated in patients with lung adenocarcinoma, HSPA5 expression did not predict the prognosis of lung adenocarcinoma patients. Notably, higher expression of HSPA5 showed higher responses to chemotherapy but not immunotherapy. Interestingly, HSPA5 expression positively correlated with ferroptosis, cellular responses to hypoxia, tumor proliferation signature, G2M checkpoint, MYC targets, and TGFB. IHC analysis also confirm the increased expression of HSPA5 in metastatic LSCC patients in our cohort. And higher expression of HSPA5 in metastatic LSCC patients demonstrated shorter PFS and overall survival time (OS). Conclusions: This study shows that ferroptosis-related gene HSPA5 expression is a negative prognostic marker for LSCC.