Biotransformation-derived metabolites from Astragalus membranaceus and Cordyceps militaris alleviate hyperuricemia via multi-target regulation

Hyperuricemia is a common metabolic disorder, and current pharmacological treatments are often associated with adverse effects. This study evaluated the anti-hyperuricemic activity of an ethanol extract obtained from bidirectional solid-state fermentation of Astragalus membranaceus and Cordyceps militaris (AMC-BFE) in a mouse model induced by potassium oxonate and adenine. AMC-BFE treatment significantly lowered serum uric acid levels, suppressed xanthine oxidase (XOD) activity, and ameliorated markers of liver and kidney function, including alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and serum creatinine. Reductions in serum total cholesterol and triglycerides were also observed. Gene expression analysis revealed transcriptional downregulation of renal urate reabsorption transporters URAT1 and GLUT9, along with altered expression of hepatic ABCG2 following AMC-BFE treatment. In addition, AMC-BFE activated the hepatic peroxisome proliferator-activated receptor-α (PPARα) signaling pathway. Chemical profiling by LC-MS/MS showed that bidirectional fermentation enriched several bioactive metabolites, including isoflavone aglycones, nucleosides, and polyols. These compositional differences may be related to the observed urate-lowering activity, although the contribution of individual metabolites requires further investigation. Untargeted metabolomics further identified alterations in gut microbiota-derived metabolites linked to antioxidant pathways. Collectively, these results suggest that AMC-BFE alleviates hyperuricemia primarily by inhibiting uric acid production and reabsorption, and that fungal biotransformation may enhance the generation of bioactive small molecules from traditional medicinal materials.