Genetic and network evidence that coffee-derived 7-methylxanthine mitigates myopia via the EPHB4 axis

Purpose: To evaluate the causal effects of coffee-related circulating biomarkers on myopia and to nominate plausible biological mechanisms. Design: Leveraging a two-sample Mendelian randomization (MR) framework, this study integrated in silico network pharmacology, gene-level MR, and computational structure-based modeling to investigate the relationship. Methods: We performed MR for 11 coffee-associated biomarkers using summary-level genome-wide association data. Predicted targets of 7-methylxanthine (7-MX) were intersected with myopia-associated genes to construct a protein–protein interaction network, identify hub genes, and conduct GO/KEGG enrichment. Gene-level MR was applied to prioritize causal candidates. The interaction between 7-MX and the key target was evaluated by molecular docking and explored by molecular dynamics (MD) simulations. Results: Genetically predicted 7-MX showed a protective association with myopia (OR 0.77; 95% CI 0.62–0.95; P = 0.014), whereas other biomarkers were null. Overlapping genes were enriched in angiogenic and signaling pathways, including VEGF and PI3K–Akt. Among hub genes, EPHB4 was prioritized; higher genetically predicted EPHB4 expression was associated with a lower myopia risk (OR 0.90; 95% CI 0.84–0.97; P = 0.005). Docking indicated stable 7-MX binding within the EPHB4 ATP pocket, which was supported by MD trajectories. Conclusions: Convergent genetic, network, and computational evidence suggests a protective role of 7-MX against myopia, potentially mediated by direct engagement of EPHB4 and modulation of angiogenic signaling. These findings are hypothesis-generating and warrant replication in larger genome-wide association studies and functional validation in ocular models.