Network Pharmacology-Based Exploration: Non-Targeted Metabolites of Lactobacillus-Fermented Chaenomeles speciosa (Sweet) Nakai, Smilax glabra Roxb. and Pueraria montana var. Lobata in Uric Acid Metabolism Intervention

Background: Previous studies have demonstrated that numerous medicine and food homology (MFH) possess the potential to regulate purine metabolism disorders, promote uric acid excretion, and alleviate hyperuricemia symptoms. Examples include CS ( Chaenomeles speciosa (Sweet) Nakai ), SR ( Smilax glabra Roxb. ) and PL ( Pueraria montana var. lobata ). Methods: Metabolomics was employed to analyze the compositional changes in medicinal and edible extracts before and after fermentation. Network pharmacology and molecular docking studies were further utilized to elucidate the interactions between these differential metabolites and the core targets of hyperuricemia. In vitro enzyme activity assays were conducted to confirm the therapeutic effects. Results: A total of 283, 248, and 18 differential metabolites were identified in CS,SR and PL samples, respectively. Among these, 54 significantly upregulated differential metabolites were selected for screening. Based on these metabolites, 53 HUA-related targets were identified for CS, SR and PL. Functional enrichment analysis revealed their roles in inflammatory stress and uric acid production pathways, particularly the MAPK signaling pathway and purine metabolism regulated by XDH. Additionally, other targets in the purine metabolism pathway, such as ADA, PNP, AMPD3, and IMPDH2, were co-regulated. Enzyme activity assays indicate that fermented MFH more effectively inhibits XOD, thereby regulating the conversion of xanthine and hypoxanthine into uric acid. Molecular docking revealed two significantly upregulated compounds in CS ; and five in PL; and four in SR. exhibit strong binding to XOD. Conclusion: These findings provide theoretical support for FMFH as a potential effective component in preventing and treating hyperuricemia. Our research demonstrates that FMFH targets multiple pathways associated with hyperuricemia, offering a promising approach for preventing this condition. Keywords: MFH, LAB, HUA, UA, network pharmacology, metabonomics