Distinct anti-hyperuricemia mechanisms of polysaccharide-rich and non-polysaccharide fractions from Lentinula edodes water extract

: Hyperuricemia (HUA) is associated with excessive uric acid (UA) production, impaired excretion, and systemic metabolic disturbances. This study investigated the differential anti-HUA mechanisms of two fractions derived from Lentinula edodes ( L . edodes ) water extract (LEW): the ethanol-supernatant fraction (non-polysaccharide, LEPS) and the ethanol-precipitated fraction (polysaccharide-rich, LEP). Physicochemical characterization revealed marked compositional differences between the two fractions. LEP was highly enriched in carbohydrates (83.36%) and mainly consisted of heterogeneous high-molecular-weight polysaccharides, whereas LEPS contained a lower carbohydrate content (34.35%) and was dominated by low-molecular-weight constituents (M w =5.20 × 10 2 g/mol). In HUA rats, LEPS exhibited superior UA-lowering efficacy, primarily attributed to potent inhibition of hepatic xanthine oxidase (XOD) activity, thereby suppressing UA production, along with marked amelioration of liver injury. In contrast, LEP played a major role in ameliorating renal injury, oxidative stress, and inflammation. Mechanistically, LEP effectively downregulated renal reabsorption transporters (URAT1, GLUT9), upregulated secretory transporters (OAT1, ABCG2), and enhanced intestinal barrier integrity via upregulating tight junction proteins. Multi-omics analysis revealed that LEPS mainly modulated amino acid and redox-related metabolic pathways (tyrosine, nicotinate metabolism), whereas LEP predominantly regulated lipid metabolism and inflammation-associated pathways (linoleic acid, arachidonic acid metabolism). Both fractions reshaped gut microbiota composition and increased total short-chain fatty acids (SCFAs) as well as specific beneficial bacteria such as Lachnospiraceae . In conclusion, L. edodes fractions exerted anti-HUA effects through differentiated mechanisms, supporting their targeted utilization in functional products for HUA management.