Identification and comprehensive analysis of ferroptosis-related genes as potential biomarkers for the diagnosis and treatment of proliferative diabetic retinopathy by bioinformatics methods

Abstract

Diabetic retinopathy (DR) is the most common retinal vascular disease. Proliferative DR (PDR) is the aggressive stage of DR with angiogenesis as a pathological hallmark, which is the main cause of blindness. There is growing evidence that ferroptosis plays a vital role in diabetics as well as its complications including DR. However, the potential functions and mechanisms of ferroptosis have not been completely elucidated in PDR. The ferroptosis-related differentially expressed genes (FRDEGs) were identified in GSE60436 and GSE94019. Then we constructed a protein-protein interaction (PPI) network and screened ferroptosis-related hub genes (FRHGs). The GO functional annotation and the KEGG pathway enrichment analyses of FRHGs were performed. The miRNet and miRTarbase databases were applied to construct the ferroptosis-related mRNA-miRNA-lncRNA network, and the Drug-Gene Interaction Database (DGIdb) was used for predicting potential therapeutic drugs. Finally, we identified 21 upregulated and 9 downregulated FRDEGs, among which 10 key target genes (P53, TXN, PTEN, SLC2A1, HMOX1, PRKAA1, ATG7, HIF1A, TGFBR1, and IL1B) were recognized with enriched functions, mainly relating to responses to oxidative stress and hypoxia in biological processes of PDR. HIF-1, FoxO and MAPK signalling may be the main pathways that influence ferroptosis in PDR. Moreover, a mRNA-miRNA-lncRNA network was constructed based on the 10 FRHGs and their co-expressed miRNAs. Finally, potential drugs targeting 10 FRHGs for PDR were predicted. Results of the receiver operator characteristic (ROC) curve indicated, with high predictive accuracy in two testing datasets (AUC>0.8), that ATG7, TGFB1, TP53, HMOX1 and ILB1 had the potential to be biomarkers of PDR.