Integrating Metabolomics and Network Pharmacology to Explore the Active Compounds and Mechanism of Fructus Gardenia in Hyperuricemia

Hyperuricemia (HUA) is becoming increasingly prevalent, and is associated with kidney dysfunction, metabolic issues, and heart disease. Fructus Gardenia (FG) has demonstrated a dual action of inhibiting uric acid (UA) production and enhancing its excretion, showing promise for treating HUA. We herein employ a combination of metabolomics and network pharmacology to explore the bioactive compounds and underlying mechanisms of FG in HUA. Upon oral administration of FG to HUA rats, serum UA levels, kidney function, and tissue changes were measured. Serum metabolomics was conducted to identify key metabolites and associated metabolic pathways. Network pharmacology and molecular docking were employed to reveal active compounds and their potential targets. Treatment with FG at a low dosage reduced the levels of UA and xanthine oxidase (XOD) to 39.7% and 54.1%, respectively, and ameliorated kidney damage induced by HUA. Xanthine dehydrogenase (XDH), hypoxanthine-guanine phosphoribosyltransferase (HPRT1), purine nucleoside phosphorylase (PNP), catalase (CAT), and glycogen phosphorylase-liver form (PYGL) were identified as the potential gene targets, which were linked to purine metabolism, inflammation, and oxidative stress. The activity of HPRT1, PNP, and PYGL was restored by FG administration, as well as the mRNA expression of P2X purinoceptor 7 (P2X7R) and solute carrier family 22 member 12 (SLC22A12). FG improves purine metabolism, reduces inflammation, and mitigates the risk of renal damage. These effects are achieved through the combined action of various compounds, including quercetin and ethyl oleate, involving the regulation of P2X7R and SLC22A12 expression, as well as the activities of XOD, HPRT1, PNP, and PYGL. PRACTICAL APPLICATIONS: As a natural food pigment, FG can be used to treat HUA and protect the kidney from damage caused by high UA levels, which is safe and effective within the recommended dosage. With further development into solid beverages or oral liquids, FG as a potential functional food and dietary supplement would meet the growing demand for natural management of UA.