Gout, an arthritic condition primarily caused by hyperuricemia, is characterized by frequent pain and swelling of the joints. In this study, we aimed to evaluate whether hemoglobin concentration causally influences gout incidence. Furthermore, we investigated the potential mediating role of plasma metabolites in this relationship, thereby providing novel insights into the mechanisms underlying gout pathogenesis and informing strategies for its prevention and treatment.

 In this Mendelian randomization analysis of genome-wide association data, representative single-nucleotide polymorphisms were selected as instrumental variables. Sensitivity analyses assessed heterogeneity, pleiotropy, and stability using weighted Egger regression, weighted median, simple mode, and weighted mode methods. Additionally, mediation Mendelian randomization was conducted to estimate the indirect effect of hemoglobin concentration on gout risk via plasma metabolites. This comprehensive approach ensured robust causal inference by validating genetic instruments through multiple statistical frameworks while explicitly quantifying the specific metabolic pathways through which hemoglobin levels influence gout susceptibility, thereby providing deeper insights into the underlying biological mechanisms connecting hematological traits with inflammatory arthritis outcomes.

Mendelian randomization analysis revealed a significant causal relationship between hemoglobin concentration and gout risk (P < 0.05), with no evidence of heterogeneity or horizontal pleiotropy detected (P > 0.05). Sensitivity analyses, including funnel plots and leave-one-out tests, robustly confirmed the stability of these findings against potential outliers. The Steiger direction test further supported the proposed causal direction (P < 0.05), indicating that hemoglobin primarily influences gout susceptibility rather than vice versa. Mediation analysis additionally suggested that hemoglobin exerts its effect on gout risk partly through modulating plasma metabolite levels. Collectively, these rigorous statistical validations strengthen the inference that elevated hemoglobin is a genuine causal factor for gout, operating through specific metabolic intermediates while satisfying key instrumental variable assumptions without bias from confounding genetic effects.

In conclusion, this Mendelian randomization study provides evidence that genetically predicted higher hemoglobin concentration may increase the risk of gout, and this causal effect is partially mediated through specific plasma metabolites. These findings suggest a potential causal pathway from hemoglobin concentration to gout pathogenesis via metabolic alterations, which may help design further research to elucidate the underlying molecular mechanisms.