To reconcile inconsistent observational and genetic evidence regarding tea consumption and urate-related outcomes by identifying metabolic mediators and shared genetic signals, and by validating the inferred pathway experimentally.

We analysed tea intake in the UK Biobank prospective cohort (primary epidemiologic analysis) with external validation in NHANES. In a UK Biobank multi-omics subset with plasma NMR metabolomics and genotype data, we applied an ensemble machine-learning feature selection strategy to prioritise tea-associated metabolites. We assessed mediation effects and performed two-sample and multivariable Mendelian randomization, followed by Bayesian colocalization to identify shared genetic signals between the prioritised metabolite(s) and serum urate. Functional relevance was evaluated using tissue expression resources and an independent PBMC transcriptomic cohort, complemented by in vitro macrophage experiments and murine models of gout and hyperuricemia.

Tea intake showed a non-linear inverse association with incident gout, with an apparent threshold around ≥6 cups/day. Among 251 NMR traits, the proportion of n-6 polyunsaturated fatty acids (n-6 PUFA; % of total fatty acids) emerged as the dominant mediator, explaining a substantial fraction of the tea-hyperuricemia and tea-gout associations. Genetically predicted higher n-6 PUFA proportion was associated with lower serum urate and reduced gout risk, and multivariable MR suggested that the n-6 PUFA-gout association operated predominantly through serum urate. Colocalization supported a shared genetic signal at the NUDC locus for n-6 PUFA proportion and serum urate. NUDC showed higher expression in kidney cortex and liver and was downregulated in PBMCs from gout patients. The tea catechin epigallocatechin gallate (EGCG) attenuated monosodium urate crystal-induced inflammatory responses, restored intracellular n-6 PUFA depletion in macrophages, and mitigated gouty arthritis and hyperuricemia in mice.

These findings support a metabolite-centric pathway linking tea intake to improved urate homeostasis through n-6 PUFA composition and a shared genetic signal at the NUDC locus, highlighting a lipid-urate axis that may inform preventive or therapeutic strategies for hyperuricemia and gout.