Identification and validation of druggable targets for cataract using mendelian randomization: functional insights from multi-omics and an oxidative stress model.

OBJECTIVE

To identify druggable genes associated with cataract and investigate their functional roles under oxidative stress, thereby providing potential therapeutic targets.

METHODS

Multi-omics data were integrated, and expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) analyses, along with Mendelian randomization (MR), were performed to assess the causal relationships between gene/protein expression and cataract risk. Phenome-wide association studies (PheWAS), the creation of protein-protein interaction networks, drug prediction, and molecular docking were further performed to evaluate their functional relevance and potential for drug development. In addition, an oxidative stress model was established by treating SRA01/04 lens epithelial cells with H2O2, and cell viability, proliferation, apoptosis, and hub gene expression were assessed using CCK8, EdU, flow cytometry, and qPCR.

RESULTS

Among 2,532 drug-associated genes, 35 eQTL genes and 31 pQTL genes were identified, with DKK3, GSTM1, and KIR2DS4 showing significant associations in both analyses. PheWAS revealed no major adverse effects, and drug prediction and molecular docking suggested GSTM1 as the most promising target. In vitro, H2O2 suppressed SRA01/04 cell viability and proliferation while promoting apoptosis in a dose-dependent manner. qPCR results showed that oxidative stress upregulated DKK3 and downregulated GSTM1 expression, both in a dose-dependent manner, consistent with MR findings, supporting DKK3 as a risk factor and GSTM1 as a protective factor for cataract.

CONCLUSION

This study identified and validated DKK3 and GSTM1 as key genes in cataract pathogenesis. By integrating genetic analyses with functional experiments, our findings provide new insights into the molecular mechanisms of cataract and establish a theoretical basis for drug development and repurposing.