Mechanistic insights into metformin's anti-hyperuricemic effect: Targeting PPP/DNPB/XOD-mediated purine pathway, purinosome assembly, and gut microbiota homostasis in rats.

Hyperuricemia has become a public threat to human health, and conventional medical treatment only aims to inhibit xanthine oxidase (XOD). Endogenous purine biosynthesis and purinosome formation are neglected in research of medical mechanism. In this study, the therapeutic effect and mechanism of metformin was explored in chronic high-fructose-induced hyperuricemic rats. Results indicated that four weeks of metformin administration effectively reduced uric acid (UA), creatinine, and urea levels, ameliorated renal and hepatic injuries, and promoted glycogen synthesis in hyperuricemic rats. Furthermore, metformin remarkedly downregulated the mRNA and protein expression of core enzymes in pentose phosphate pathway (PPP), and de novo purine biosynthesis (DNPB) of endogenous purine. Metformin was found to markedly inhibit the purine salvage pathway (PSP) and XOD to retard purine recycling and metabolism. Additionally, metformin effectively restored physiological purinosome architecture, preventing aberrant enzyme clustering and subcellular redistribution. The hepatic levels of IMP, inosine, hypoxanthine and xanthine in hyperuricemic rats were remarkably decreased by metformin. Besides, metformin favorably maintained the gut microbiome homeostasis and normalized purine metabolism to lower purine levels in intestine. Taken together, the results for the first time indicated that metformin exerted appreciable anti-hyperuricemic effect, at least partly, via inhibiting original biosynthetic and metabolic pathways of endogenous purine simultaneously mediated by PPP/DNPB/XOD, purinosome assembly, and modulating gut microflora profile. This work provided a scientific basis for its potential application in hyperuricemia therapy beyond its classical use in diabetes.