Identification and Validation of a GPX4-Related Immune Prognostic Signature for Lung Adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) is a commonly occurring histological subtype of lung cancer. Glutathione peroxidase 4 (GPX4) is an important regulatory factor of ferroptosis and is involved in the development of many cancers, but its prognostic significance has not been systematically described in LUAD. In this study, we focused on developing a robust GPX4-related prognostic signature (GPS) for LUAD. Data for the training cohort was extracted from The Cancer Genome Atlas, and that for the validation cohort was sourced from the GSE72094 dataset including 863 LUAD patients. GPX4-related genes were screened out by weighted gene coexpression network analysis and Spearman’s correlation analysis. Then, Cox regression and least absolute shrinkage and selection operator regression analyses were employed to construct a GPS. The ESTIMATE algorithm, single-sample gene set enrichment analysis (ssGSEA), and GSEA were utilized to evaluate the relationship between GPS and the tumor microenvironment (TME). We constructed and validated a GPS premised on four GPX4-related genes (KIF14, LATS2, PRKCE, and TM6SF1), which could classify LUAD patients into low- and high-score cohorts. The high-risk cohort presented noticeably poorer overall survival (OS) as opposed to the low-risk cohort, meaning that the GPS may be utilized as an independent predictor of the OS of LUAD. The GPS was also adversely correlated with multiple tumor-infiltrating immune cells and immune-related processes and pathways in TME. Furthermore, greater sensitivity to erlotinib and lapatinib were identified in the low-risk cohort based on the GDSC database. Our findings suggest that the GPS can effectively forecast the prognosis of LUAD patients and may possibly regulate the TME of LUAD.

Machine-learning developed an iron, copper, and sulfur-metabolism associated signature predicts lung adenocarcinoma prognosis and therapy response

“…Additionally, treatment with the ferroptosis inhibitor ferrostatin-1 efficiently restored the balance of macrophage polarization disrupted by RRM2 inhibition [ 42 ]. Furthermore, the significant correlation between two ICSMRGs, namely KIF14 and PEBP1, and GPX4—a lipid peroxidase known for its ability to trigger ferroptosis—suggests a clear association between these genes and the ferroptotic process [ 43 , 44 ]. The effects of some ICSMRGs on iron, copper, and sulfur metabolism have not been determined, but some studies suggest that they may be involved in the development of LUAD, such as SERPINB5 stimulates proliferation, metastasis, and EMT in LUAD, while elevated DDIT4 expression correlates with an unfavorable prognosis in LUAD [ 45 , 46 ].…”

Novel roles for HMGA2 isoforms in regulating oxidative stress and sensitizing to RSL3-Induced ferroptosis in prostate cancer cells

“…Upregulated gene ACSBG1 in HMGA2-TR cells is reported to be a pro-ferroptotic factor in heat-induced ferroptosis for cancer therapy [ 69 ]. TM6SF1 upregulated in HMGA2-TR cells is shown to be a ferroptosis related gene in lung adenocarcinoma [ 70 ]. FTH1 gene is downregulated in both HMGA2-WT and -TR cells; this encodes a member of ferritin that is an iron storage and antioxidant molecule and regulates ferroptosis [ 68 , 71 ].…”

Regulation of Ferroptosis in Lung Adenocarcinoma

“…Patients with a higher abundance of these ferroptosis-related TME cell subtypes have a better clinical outcome [53]. In addition, ferroptosis-related prognostic signatures, such as the prognostic ferroptosis-related lncRNA signature and GPX4-related prognostic signature, are not only correlated with multiple tumor-infiltrating immune cells and immune-associated processes and pathways in TME, but also with the response to immunotherapy, chemotherapy, and targeted therapy [57,58].…”