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Accumulating evidence suggests that dietary fructose has a close relationship with metabolic diseases like hyperuricemia (HUA). However, the role and metabolic fate of fructose intake remain elusively obscure. The present work made a pioneering endeavor to unravel the potential mechanistic link between prolonged fructose overconsumption and the incidence of HUA. High\u2010fructose (30%) free drinking was provided to rats for 17 weeks. Results indicated that long\u2010term high\u2010fructose intake remarkably increased the levels of uric acid, creatinine, and urea. Besides, mild renal alteration induced by high fructose was observed in the hyperuricemic rats. Instead of activating ketohexokinase, high\u2010fructose intake activated the pentose phosphate pathway (PPP) to produce abundant ribose 5\u2010phosphate and phosphoribosyl pyrophosphate. The de novo purine biosynthesis (DNPB) was activated to produce purines and accelerate the purine cycle. High\u2010fructose intake significantly enhanced the expression of core enzymes of DNPB and changed the purinosome formation and forming areas. Furthermore, up\u2010regulation of xanthine oxidase (XOD) promoted the purine metabolism, resulting in increased levels of inosine monophosphate, inosine, hypoxanthine, and xanthine. Besides, the targeted metabolome analysis also showed that fructose metabolism triggered bioenergetic alteration with the consumption of ATP and a surge in NAD\n                    <jats:sup>+<\/jats:sup>\n                    and NADH. Hence, chronic ingestion of high\u2010fructose contributed to HUA, which was intimately associated with activation of original biosynthetic and metabolic pathways of endogenous purine simultaneously mediated by PPP, DNPB, and XOD and accompanied by bioenergetic alteration.\n                  <\/jats:p>","DOI":"10.1002\/mnfr.70122","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:27:19Z","timestamp":1748564839000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Prolonged Fructose Overconsumption Activates Original Biosynthetic and Metabolic Pathways of Endogenous Purine in Rats"],"prefix":"10.1002","volume":"69","author":[{"given":"Qiuxia","family":"Yu","sequence":"first","affiliation":[{"name":"The Second Clinical College of Guangzhou University of Chinese Medicine Guangzhou China"},{"name":"School of Pharmacy Fudan University Shanghai 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