Genetic and Network Pharmacology Insights of Chlorogenic Acid in Coffee on Kidney Stones

Objective To investigate how chlorogenic acid treats urinary tract stones, we first use a two-step Mendelian randomization (MR) approach to explore the impact of coffee on 4782 serum proteins related to upper urinary tract stones. We also apply network pharmacology to assess the effects of two active caffeoylquinic acids in coffee on kidney stones and identify potential therapeutic targets. Methods 1.Database Selection: GWAS data for coffee consumption from UKBB and data on upper urinary tract stones from FinnGen were used, focusing on European populations. 2.Selection of Genetic Instrument Variables: SNPs were carefully screened to ensure accurate and robust causal inference. 3.MR Statistical Analysis: Various methods, including TSMR, multivariable MR, and mediator MR, were employed to assess causal relationships. 4.Network Pharmacology Analysis: Potential targets of chlorogenic acid in coffee were predicted to identify common pathways and synergistic targets. Results TSMR results show that coffee intake protects against urinary tract stones, with robust findings after removing outliers and no confounders identified. Reverse MR did not find a significant causal link between coffee and upper urinary tract stones. Multivariable MR showed a significant effect of coffee on these stones, but no effect from caffeine levels. Coffee intake was weakly associated with caffeine. Mediator MR identified 35 significant serum proteins with mediation effects. Network pharmacology and previous studies suggest that chlorogenic acid in coffee may protect against kidney stones by inhibiting ANP32A and its partner APEX1. Conclusion Chlorogenic acid in coffee impacts the pathogenesis of upper urinary tract stones by modulating the expression and synergistic action of APEX1 and ANP32A.