Identification of key ferroptosis-related genes associated with the development of gastric cancer: Prognostic models, molecular mechanisms and potential treatment strategies

Ferroptosis is a novel iron-dependent form of cell death that influences the development and progression of gastric Cancer (GC), affecting its growth, invasion and metastasis. However, molecular regulatory mechanisms of Ferroptosis in GC remain unclear. The present study aimed to identify key ferroptosis-related genes associated with GC development. Ferroptosis-related genes were collected from FerrDb, a database that collects data on genes and substances that regulate Ferroptosis, and the top survival-related genes (including progression-free and overall survival), and differentially expressed genes were identified using data from The Cancer Genome Atlas stomach adenocarcinoma (STAD) samples. Following intersection analysis, least absolute shrinkage and selection operator analysis was performed on 140 screened important genes, and 14 key ferroptosis-related genes in STAD were obtained using COX regression models. By reviewing the expression of these genes through the Gene Set Cancer Analysis tool and their correlation with survival, the present study analyzed their overall role in STAD. Tumor immunity analysis was performed to identify potential MicroRNAs (miRs) and drugs targeting key carcinogenic Ferroptosis genes in STAD. NADPH Oxidase (NOX) 4, NOX5, aldo-keto reductase family 1 member C2, RNA binding motif single stranded interacting protein 1 (RBMS1), GABA type A receptor associated protein like 2 (GABARAPL2), Gap Junction Protein α1 (GJA1), transferrin and hydroxycarboxylic acid receptor 1 were notable risk genes. Additionally, by examining the association between these genes and tumor-infiltrating immune cells, it was discovered that GABARAPL2, GJA1, NOX4 and RBMS1 may influence the immune microenvironment. In total, five miRs [Homo sapiens (hsa)-miR-6795-5p, hsa-miR-6758-5p, hsa-miR-501-5p, hsa-miR-505-5p and hsa-miR-484] with potential therapeutic implications for STAD were identified as targeting carcinogenic genes. Finally, using the Genomics of Drug Sensitivity in Cancer and Cancer Therapeutics Response Portal databases, potential drugs [(5Z)-7-oxozeaenol, selumetinib, RDEA119, AZ628, dabrafenib and trametinib] were identified based on the aforementioned seven key carcinogenic genes, focusing on those that targeted multiple genes. In conclusion, the present study identified 14 key ferroptosis-related genes, and seven key carcinogenic genes, which represent promising novel molecular targets for the prognosis and treatment of GC.

ferroptosis; gastric cancer; prognostic model; stomach adenocarcinoma; tumor immunity.