Ferroptosis-mediated primary open-angle glaucoma: Insight from gene signature and identification of potential small-molecule drugs

Background Recent studies have found that ferroptosis may be involved in the process of trabecular meshwork injury in glaucoma. This study aims to reveal ferroptosis-related gene signature in primary open-angle glaucoma (POAG) and identify small molecule drugs as new direction of therapy. Methods Ferroptosis-related indicators in POAG patients and chronic ocular hypertension (COH) rats were detected by ELISA kits. The dataset (GSE27276) from GEO database and ferroptosis-related genes from FerrDb were downloaded for analysis. Small molecule drugs targeting ferroptosis-related signature components were predicted via CMap database and CB-Dock2. H ₂ O ₂ -induced human trabecular meshwork cells (HTMCs) oxidative stress model was constructed to validate the expression of hub genes and efficacy of drugs. Digoxin was made into eye drops to verify its intraocular pressure (IOP) lowering effect in vivo. Results Ferroptosis levels were enhanced in POAG patients and COH eyes of rats. A total of 14 ferroptosis-related differentially expressed genes were identified. PPI analysis and in vitro experiments showed HBA1, SLC2A3 and SCD played an important role in ferroptosis-mediated POAG. CMap and molecular docking indicated that ATPase inhibitors digoxin might be considered as potential therapeutic drugs for POAG. Digoxin administration alleviated H ₂ O ₂ -induced HTMCs ferroptosis and lowered IOP of COH eyes. Conclusions This study clarified the ferroptosis-related gene signature in the pathogenesis of POAG, which provide a theoretical basis for the prevention and early diagnosis of POAG. Translation of specific small molecule drugs will propose new ideas for therapy of POAG.