Identification and validation of a novel ferroptosis-related gene signature associated with inherited retinal degeneration in Rd10 mice.

Abstract

Retinitis pigmentosa (RP) is among the most irreversible inherited blindness diseases. Previous evidences have demonstrated that ferroptosis plays a significant role in various neurodegenerative diseases. Thus, elucidating the relationship between ferroptosis and retinitis pigmentosa may yield valuable insights for identifying therapeutic targets for inherited retinal degeneration. In the current study, a public dataset of GSE56473 from the Gene Expression Omnibus (GEO) database was analysed to identify the differentially expressed ferroptosis related genes (DE-FRGs) within the degenerative retinas between Rd10 mice and control individuals. Gene Ontology (GO), Kyoto Encyclopedia of Genomes (KEGG) and protein-protein interaction (PPI) network analyses were performed on these DE-FRGs. Hub ferroptosis-related genes (HFRGs) were subsequently identified using multiple bioinformatic algorithms. Changes in the expression profiles of the identified HFRGs were validated through the GSE178928 dataset. Immunofluorescence staining, quantitative PCR (qPCR) and a single cell sequencing dateset analysis were performed to evaluated the expression patterns of several HFRGs in the Rd10 mice. Furthermore, potential target drugs were predicted utilizing the DGIdb database. In total, 37 ferroptosis-related genes were identified among the 2096 differentially expressed genes, which were enriched in several biological processes including the response to oxidative stress, positive regulation of neuron death, ferroptosis and the PPAR signaling. Through protein-protein interaction network and multiple bioinformatics analyses, eight HFRGs (Egr1, Cd44, Egfr, Tlr4, Timp1, Cybb, Lcn2, and Ppara) were ultimately identified, with most being upregulated in the retinas of Rd10 mice. Among these HFRGs, Egr1 expression was significantly increased in rod and cone photoreceptors, whereas Cd44 expression was markedly upregulated in Müller cells. Several potential therapeutic compounds, such as Genipin, were also predicted. Our study provides novel biomarkers and therapeutic targets for the inherited retinal degeneration.