GAPDH Is a Novel Ferroptosis-Related Marker and Correlates with Immune Microenvironment in Lung Adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) is a prevalent form of lung cancer with high morbidity and fatality rates. Ferroptosis is a type of programmed cell death that is iron-dependent. Recent findings have suggested that ferroptosis inducers have promising prospects for the therapy of LUAD. However, ferroptosis-related gene expression in LUAD and its relationship with the tumor prognosis and tumor immune microenvironment remain unknown. We identified a total of 638 ferroptosis-related genes, built a LUAD ferroptosis-related risk model (FRRM) with the help of Least Absolute Shrinkage Selection Operator (LASSO) regression analysis based on The Cancer Genome Atlas (TCGA) database, split LUAD patients into high- and low-risk clusters, and verified the model utilizing the Gene Expression Omnibus (GEO) database. The results of the FRRM’s principal component analysis (PCA) demonstrated its strong predictive power. Further, univariate and multivariate Cox and AUC curve analyses demonstrated that the model was independent of other clinical traits and served as an independent prognostic factor. The nomogram demonstrated strong predictive power for overall survival, according to calibration plots. We also explored variations in clinical characteristics, immune cell infiltration, immune-related function, and functional pathways between the high- and low-risk groups. Additionally, we used a protein–protein interaction (PPI) network of various genes in the two groups to search for potential target genes. GAPDH was then chosen for a follow-up investigation. An analysis was performed on the relationship between GAPDH and variations in survival prognosis, clinical traits, immune cell infiltration, immune checkpoints, and immunotherapy. In vitro tests further supported the probable functions of GAPDH as a ferroptosis marker in LUAD. In conclusion, a novel ferroptosis-related prognostic gene, GAPDH, was discovered, whose expression was connected to the tumor immune microenvironment. The combination of immunotherapy and the targeting of GAPDH to induce ferroptosis in LUAD may provide a novel therapeutical option.