Identification of key ferroptosis genes in diabetic retinopathy based on bioinformatics analysis

Diabetic retinopathy (DR) is a retinal microvascular disease associated with diabetes. Ferroptosis is a new type of programmed cell death that may participate in the occurrence and development of DR. Therefore, this study aimed to identify the DR ferroptosis-related genes by bioinformatics methods.

The RNAseq data of DR and healthy control retinas were downloaded from the gene expression synthesis (GEO) database and analyzed using the R package DESeq2. The key modules were obtained using the WGCNA algorithm, and their genes were intersected with ferroptosis-related genes in the FerrDb database to obtain differentially expressed ferroptosis-related genes (DE-FRGs). Enrichment analysis was conducted to understand the function and enrichment pathways of ferroptosis genes in DR, and hub genes were identified by protein-protein interaction (PPI) analysis. The diagnostic accuracy of hub genes for DR was evaluated according to the area under the ROC curve. The TRRUST database was then used to predict the regulatory relationship between transcription factors and target genes, with the mirDIP, ENCORI, RNAnter, RNA22, miRWalk and miRDB databases used to predict the regulatory relationship between miRNAs and target genes. Finally, another data set was used to verify the hub genes.

In total, 52 ferroptosis-related DEGs (43 up-regulated and 9 down-regulated) were identified using 15 DR samples and 3 control samples and were shown to be significantly enriched in the intrinsic apoptotic signaling pathway, autophagosome, iron ion binding and p53 signaling pathway. Seven hub genes of DR ferroptosis were identified through PPI network analysis, but only HMOX1 and PTGS2 were differentially expressed in another data set. The miRNAs prediction showed that hsa-miR-873-5p was the key miRNA regulating HMOX1, while hsa-miR-624-5p and hsa-miR-542-3p were the key miRNAs regulating PTGS2. Furthermore, HMOX1 and PTGS2 were regulated by 13 and 20 transcription factors, respectively.

The hub genes HMOX1 and PTGS2, and their associated transcription factors and miRNAs, may be involved in ferroptosis in diabetic retinopathy. Therefore, the specific mechanism is worthy of further investigation.