To systematically clarify the bidirectional causal relationship between genetically predicted gout and NAFLD risk, and to identify key mediating molecules, biological pathways and regulatory networks driving this association. By integrating large-scale genetic data, multi-omics resources and clinical biomarkers, this study aims to uncover the pathological links between gout and NAFLD, and to validate potential mediators and therapeutic targets, thereby laying a foundation for precision prevention and treatment of NAFLD in gout patients.

Leveraging large-scale genome-wide association study (GWAS) data from European populations, we employed two-sample Mendelian randomization (MR) to rigorously assess bidirectional causality between genetically predicted gout and NAFLD, adjusting for potential confounding factors and ensuring causal inference. We further integrated multi-omics data (including transcriptomic, metabolomic and proteomic datasets) and clinical biomarkers to conduct mediation analysis and dissect the intermediate steps. Additionally, by combining multidimensional genetic methods such as summary-data-based Mendelian randomization (SMR) and colocalization analysis, we screened for candidate mediating molecules and enriched biological pathways. Key proteins and candidate genes were then validated in independent clinical cohorts and real-world clinical samples to verify the reliability and robustness of our findings.

Genetically predicted gout was found to significantly increase the risk of incident NAFLD, providing robust causal evidence for the adverse impact of gout on NAFLD development. Conversely, no statistical support was found for a reverse causal relationship from NAFLD to gout. Further mediation analysis revealed that this causal effect was partially mediated by a series of proteins and metabolites, with core pathways converging on inflammation-immune activation, oxidative stress response, and hepatic metabolic reprogramming. Validation in independent clinical samples further confirmed the clinical relevance and reliability of these key mediators, highlighting their potential as novel diagnostic and predictive biomarkers for NAFLD in gout populations.

This study systematically reveals the causal role of gout in NAFLD development and its underlying mediating mechanisms from genetic and molecular perspectives. The findings elucidate the pathological link between gout and NAFLD, and provide an important basis for NAFLD risk assessment, early screening and precise intervention in gout patients.