Decoding coffee's chlorogenic acid: genetic-network pharmacology insights on kidney stones

Chlorogenic acid, a principal bioactive component of coffee, has been proposed to reduce the risk of urinary tract stones, though its underlying mechanisms remain unclear. This study integrated Mendelian randomization and network pharmacology approaches to investigate its potential therapeutic role. A two-step Mendelian randomization analysis was conducted using genome-wide association data from the UK Biobank (coffee intake) and Finngen (upper urinary tract stones), focusing on European populations. Instrumental variables were rigorously selected to ensure valid causal inference. Coffee intake was significantly associated with a reduced risk of urinary tract stones, independent of caffeine levels, and this association remained robust across multiple analytical models. Mediation analysis identified 35 serum proteins potentially involved in this relationship. To explore the molecular mechanisms, two major caffeoylquinic acid isomers in coffee were examined through network pharmacology. ANP32A and its interacting protein APEX1 emerged as key targets, both implicated in oxidative stress and inflammation pathways relevant to stone pathogenesis. These findings suggest that chlorogenic acid may exert protective effects against urinary tract stones by modulating specific proteins and biological pathways, offering insight into potential preventive strategies.