Pan-Cancer Analysis of the Role of the Ferroptosis-Related Biomarker GPX4: A Potential Target for Prognosis and Immunotherapy

Abstract

Background Glutathione peroxidase 4 (GPX4) is a key player in ferroptosis. The aim of the study is to explore the underlying mechanisms and biological functions of GPX4 to provide therapeutic guidance for the treatment of cancer.Methods The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression database (GTEx), GEPIA2, cBioPortal databases, and Human Protein Atlas (HPA) were explored to analyze the expression, mutation, and prognosis of GPX4 in human tumors. TIMER2.0 and TIDE were used for immune evaluations. GPX4 expression profile at single-cell level was evaluated through CancerSEA.Results GPX4 was aberrantly expressed in most cancer types. Higher GPX4 was correlated with worse overall survival (OS) in colon adenocarcinoma (COAD), acute myeloid leukemia (LAML) and uveal melanoma (UVM), but with better OS in breast invasive carcinoma (BRCA), thyroid carcinoma (THCA), and uterine corpus endometrial carcinoma (UCEC). Moreover, GPX4's genetic alteration and methylation levels were varied and correlated with prognosis in some cancer types. According to the results of single-cell sequencing, GPX4 expression significantly correlated to DNA damage/repair, angiogenesis, metastasis, and inflammation. Additionally, GPX4 was also strongly linked to immune infiltration (such as macrophage, cancer-associated fibroblasts, and neutrophil) and immune checkpoint expression in the tumor microenvironment (TME).Conclusions GPX4 plays an important role in the occurrence, development, and prognosis of human malignant tumors. Our comprehensive pan-cancer analyses have conveyed that GPX4 could potentially serve as a cancer treatment target and biomarker.