Oxyberberine alleviates fructose-induced hyperuricemia by modulating purine metabolism and gut microbiota

Phellodendri Chinensis Cortex, a time-honored Chinese materia medica, has long been applied in the management of gout and other diseases. Hyperuricemia (HUA) is the vital contributor for the occurrence and progression of gout. Oxyberberine (OBB), an oxidized protoberberine alkaloid, is naturally present in Phellodendri Chinensis Cortex. The work made a pioneering endeavor to unravel the potential anti-HUA effect and mechanism of OBB. Hight fructose-induced experimental HUA in rats was employed. Results indicated that OBB significantly reduced the body weight and UA level, and concurrently mitigated hepatic injury, which achieved superior therapeutic effect to its prodrug berberine (BBR). OBB treatment remarkably alleviated inflammatory response and oxidative stress. Furthermore, OBB appreciably activated the gene expression of key enzymes involved in the pentose phosphate pathway (PPP), and inhibited the transcriptional or translational expression of key enzymes in de novo purine biosynthesis (DNPB), as well as modulated purine salvage pathway (PSP), collectively leading to a reduction in UA level. Molecular docking and dynamic simulation further confirmed the dynamic stability of OBB-target protein complexes. Meanwhile, OBB favorably modulated the fructose-induced gut dysbiosis, enhanced the abundance of probiotics and abated detrimental counterparts, which were associated with promoting UA catabolism and inhibiting inflammation response via correlation analysis. In summary, our findings in pioneering endeavor found that OBB efficaciously ameliorated fructose-elicited HUA. The mechanism was intimately associated with alleviating endogenous purine original biosynthetic and metabolic pathways and favorably harmonizing gut microflora homeostatic disequilibrium. This study has uncovered innovative mechanisms underlying OBB's therapeutic potential for HUA and bolstered the scientific basis for the historical use of Phellodendri Chinensis Cortex and BBR in the management of HUA.