To explore the mechanism of carnosic acid (CA) in treating primary open angle glaucoma (POAG)-induced optic nerve injury using network pharmacology and bioinformatics analyses.

CA targets were predicted using SwissTargetPrediction and TARGET PREDICTION databases, while glaucoma-related targets were identified via GeneCards, OMIM, DisGeNET, and CTD. Differentially expressed genes (DEGs) were identified by analyzing the Gene Expression Omnibus (GEO) dataset GSE45570, which includes optic nerve head samples from 6 POAG patients and 6 controls. Key targets were derived by intersecting DEGs with CA and glaucoma targets. The expression of the key target gene, FABP3, was further validated in two independent GEO datasets: GSE13534 (lamina cribrosa cells) and GSE2387 (lamina cribrosa region samples). The expression was also validated at mRNA and protein levels using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) in experimental models. Molecular docking was used to assess binding affinity, and co-immunoprecipitation (Co-IP) confirmed the interaction. Functional enrichment and immune-infiltration correlation analyses were also performed.

A total of 306 DEGs, 84 CA targets, and 15715 glaucoma targets were identified. FABP3 was identified as the key target, which was significantly upregulated in POAG samples in both validation datasets (GSE13534 and GSE2387) and confirmed by qRT-PCR and WB assays. Molecular docking revealed a strong binding affinity between FABP3 and CA (docking score: -9.79 kcal/mol), which was validated by Co-IP. Functional enrichment analysis showed FABP3 was associated with mitochondrial function and immune-related pathways. Correlation analysis indicated FABP3 had a significant negative correlation with activated dendritic cells (aDCs).

Our study suggests that CA may treat POAG by targeting FABP3, potentially by mitigating oxidative stress and modulating immune responses. This provides a pharmacological foundation and identifies FABP3 as a potential therapeutic target for POAG treatment.

To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma (POAG) based on a Mendelian randomization (MR) study.

Large-scale protein quantitative trait loci (pQTLs) data from the Icelandic deCODE database and two large POAG Genome-Wide Association Study (GWAS) summary datasets were used in this study. Causal associations between plasma proteins and POAG were identified using summary-data-based MR (SMR) analysis and the heterogeneity in dependent instruments (HEIDI) test. Colocalization analysis was then conducted to assess the genetic associations between these two factors. Phenotype-wide MR analysis was performed to validate protein targets as potential drug targets and to evaluate potential side effects. Finally, protein-protein interactions (PPI) were studied, and the Drug-Gene Interaction Database (DGIDb) was used to identify associations between drugs and the identified proteins.

Four proteins (SVEP1, TMEM190, ROBO1, and ENPP5) were identified as potential drug targets in this study. Phenome-wide MR analysis showed that SVEP1, ROBO1, and ENPP5 were not associated with adverse effects, while TMEM190 was linked to nerve root and plexus disorders, as well as subarachnoid hemorrhage. Ticagrelor was suggested as a potential new drug for the treatment of glaucoma by regulating SVEP1.

Four plasma proteins—SVEP1, TMEM190, ROBO1, and ENPP5—are identified as potential therapeutic targets for POAG through an MR approach. Phenome-wide MR analysis reveals that SVEP1, ROBO1, and ENPP5 are not associated with adverse effects, while TMEM190 is linked to nerve root and plexus disorders, as well as subarachnoid hemorrhage. Ticagrelor is proposed as a potential therapeutic drug for glaucoma by regulating SVEP1. These findings highlight the potential of plasma proteins as drug targets for POAG and provide valuable insights for further research.