Eupalinolide I derivative (EJM) alleviates hyperuricemia by targeting STAT1 to regulate intestinal inflammation and microbiota

Background and purpose: Hyperuricemia (HUA) is increasingly recognized as a systemic disorder involving metabolic dysregulation and chronic inflammation, with emerging evidence implicating the intestine as a key extra-renal site of urate handling. However, the molecular mechanisms linking intestinal inflammation, urate transport, and immune signaling in HUA remain incompletely understood. This study aimed to evaluate the anti-hyperuricemic effects of EJM, a synthetic derivative of eupalinolide I, and to explore its potential mechanisms with a particular focus on intestinal inflammation, urate transport, and immune-related signaling pathways. Experimental Approach: HUA was induced in mice using potassium oxonate, yeast extract, and fructose. The effects of EJM were assessed via serum biochemistry, histopathology, Western blotting, and 16S rRNA sequencing. The direct target of EJM was identified using human proteome microarray and validated by cellular thermal shift assay and molecular docking. Key Results: EJM significantly reduced serum uric acid levels and alleviated pathological damage in both the kidney and small intestine. Mechanistically, protein chip technology identified STAT1 as a direct binding target of EJM. Consequently, EJM effectively suppressed the IFN-γ/JAK/STAT1 signaling pathway in the intestine, leading to reduced levels of pro-inflammatory cytokines (IFN-γ, IL-17A, IL-6, TNF-α). This anti-inflammatory effect was coupled with promotion of UA excretion: EJM modulated the expression of key uric acid transporters, especially downregulating URAT1 and GLUT9 in the kidneys and GLUT9 reabsorption proteins in the intestines, while upregulating ABCG2 in the kidneys and intestines. Furthermore, EJM restructured the gut microbiota composition and restored intestinal microbiota balance by promoting the proliferation of beneficial bacteria such as Weissalla, and reducing the abundance of Lachnospiraceae and Staphylococcaceae . Conclusion and Implication: EJM exerts anti-HUA effects by repairing kidney-intestinal tissue damage, regulating uric acid transporters, blocking the IFN-γ/JAK1/STAT1 signaling pathway, and correcting dysbiosis, thereby providing new therapeutic strategies for clinical treatment.