The Ferroptosis-Related Gene Signature and Phenotypic Identification of Potential Small-molecule Drugs in Primary Open-Angle Glaucoma

Abstract

Purpose : Recent studies have found that ferroptosis may be involved in the process of trabecular meshwork injury in glaucoma. This study aims to reveal the new mechanism of ferroptosis-mediated primary open-angle glaucoma (POAG), and to establish ferroptosis index (FPI) as a risk prediction model for POAG. Meanwhile, identification of small molecule drugs will provide a new direction of therapy for POAG.

Methods : The microarray dataset (GSE27276) was downloaded from GEO database. The differential expressed genes (DEGs) between POAG and normal were identified and intersected with ferroptosis-related genes downloaded from FerrDb. Protein-protein interaction (PPI) network and gene importance score were constructed to explore the hub genes. Principal component analysis (PCA) was implemented to extract principal component score as FPI. KEGG and GSEA was conducted to reveal main signaling pathways. ROC curves were generated to validate the effects of hub genes as biomarkers for POAG. Small molecule drugs were predicted via CMAP database. Hydrogen peroxide (H2O2)-induced human trabecular meshwork cells (HTMCs) oxidative stress model was constructed to validate the expression of hub genes.

Results : A total of 14 ferroptosis-related DEGs between control and POAG were identified. KEGG analysis showed that 14 hub genes were enriched in hypoxia response. PPI network and gene importance score showed that HBA1 may play an important role in ferroptosis-mediated POAG. FPI in POAG group showed significantly difference from that in the normal group. FPI and HBA1 displayed great effects as biomarkers for POAG (AUC=0.997). GSEA analysis showed that ferroptosis in POAG may be related to calcium signaling pathway and oxidative phosphorylation. And serotonin receptor agonist might be considered as potential therapeutic drugs for POAG. In addition, ferroptosis inhibitor Fer-1 displayed the most significant resistance to H₂O₂-induced HTMCs death and ECM remodeling compared with Nec-1and Z-VAD. H₂O₂ significantly induced differential expression of HBA1, SLC2A3, FADS2 and DDIT4.

Conclusions : This study clarified the ferroptosis-related gene signature in the pathogenesis of POAG. Construction of FPI will provide a theoretical basis for the prevention and early diagnosis of POAG. Translation of specific small molecule drugs will provide new ideas for therapy of POAG.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.