Structural divergence of lentinula edodes polysaccharides is associated with distinct anti-hyperuricemia pathways

Abstract Lentinula edodes ( L. edodes ) polysaccharides hold therapeutic potential for hyperuricemia (HUA), but their mechanisms remain unclear. This study investigated the anti-HUA effects and associated regulatory pathways of two structurally distinct polysaccharides (LEP20 and LEP50) from L. edodes . Structural analysis identified LEP20 as a (1 → 3)- β -D-glucan ( M w , 1.96×10 6 g/mol) and LEP50 as a (1 → 4)- α -D-glucan ( M w , 1.46×10 7 g/mol). In a HUA rat model, both LEP20 and LEP50 significantly reduced serum UA level, inhibited xanthine oxidase, and alleviated renal injury and inflammation. Mechanistically, LEP20 was linked to modulate the gut-kidney axis by regulating UA transporters, enriching beneficial gut microbiota (e.g., Blautia_luti ), and promoting short-chain fatty acid production to restore intestinal barrier integrity. In contrast, LEP50 primarily regulated systemic purine metabolism, directly reducing hypoxanthine levels and modulating specific gut microbes (e.g., Romboutsia_ilealis ). The distinct structural features of these polysaccharides are associated with different regulatory pathways, supporting their potential application in HUA management.