Research Mechanisms of the Uric Acid-Lowering Effects of Quercetin

1. Introduction 

Hyperuricemia, a significant risk factor for gout, kidney stones, and cardiovascular diseases, has become a globally prevalent metabolic disorder. In the study of natural products for lowering uric acid, quercetin—a widely distributed flavonol compound—has attracted considerable attention. It is primarily derived from plants such as onions, apples, hawthorn, and buckwheat, with content in Sophora japonica buds reaching about 4%. It is also found in medicinal plants like Ginkgo biloba and elderberry. Quercetin exists in glycoside or aglycone forms, releasing active components after hydrolysis. Traditionally used for its anti-inflammatory and diuretic properties, modern research has confirmed its potential to regulate purine metabolism, offering a new direction for the natural intervention of hyperuricemia.

2. Metabolism of Active Components 

Quercetin undergoes complex absorption and transformation in the body: after oral administration, it is mainly absorbed in the small intestine, where glycoside forms must be hydrolyzed by gut microbiota β-glucosidase into aglycones for effective utilization. Once absorbed, quercetin is metabolized via the hepatic cytochrome P450 enzyme system (primarily CYP3A4 and CYP2C9), producing metabolites such as dihydroquercetin and kaempferol. These metabolites are excreted mainly through urine and feces. However, its poor water solubility and short half-life result in low bioavailability, which is a key limiting factor for clinical application. Gut microbiota plays a dual role in quercetin metabolism, both facilitating hydrolysis for absorption and enhancing its activity through microbial transformation.

3. Mechanisms of Uric Acid-Lowering Effects

3.1 Inhibition of Uric Acid Production 

By binding to the FAD domain of xanthine oxidase (XOD), quercetin reversibly inhibits its activity in a mixed-type manner, reducing the conversion of xanthine to uric acid. Its inhibitory efficacy is comparable to that of allopurinol. Additionally, it downregulates adenosine deaminase (ADA) activity, blocking the purine nucleotide degradation pathway.

3.2 Promotion of Uric Acid Excretion 

In the kidneys, quercetin upregulates the expression of the ABCG2 transporter while inhibiting the reabsorption functions of URAT1 and GLUT9, thereby enhancing uric acid excretion efficiency.

3.3 Modulation of Gut Microbiota 

Quercetin enriches Lactobacillus aviarius (e.g., CML180), which degrades purine nucleotides (inosine, adenosine) via its nucleoside hydrolase (Nhy69), reducing precursors of uric acid.

4. Pharmacological Studies 

Animal studies have shown that quercetin can reduce serum uric acid levels by more than 30% in hyperuricemic mice, while also lowering creatinine and blood urea nitrogen levels and alleviating renal inflammation. Research from China Agricultural University found that quercetin intervention significantly ameliorates hyperuricemia in broilers, an effect associated with the remodeling of gut microbiota structure. In clinical studies, daily supplementation of 500 mg quercetin reduced serum uric acid by 15%–20% in hyperuricemic patients. Combined use with probiotics (e.g., Lactobacillus plantarum) enhanced efficacy by modulating glutathione and purine metabolism. In vitro experiments confirmed that quercetin-3-O-glucuronide directly regulates the expression of uric acid transporters in renal tubular cells.

5. Safety Validation 

Quercetin is well-tolerated at recommended doses (≤1000 mg/day), but high doses may cause gastrointestinal discomfort (nausea, abdominal pain), headaches, or allergic reactions. Animal studies indicate that long-term high doses (exceeding 2000 mg/kg) may affect liver and kidney function, but no significant toxicity has been observed at clinical commonly used doses. Caution is advised regarding its synergistic effects with anticoagulants, which may increase bleeding risk. It should be used cautiously in pregnant women and individuals with impaired liver or kidney function.

6. Summary and Outlook 

Quercetin exerts its uric acid-lowering effects through a triple mechanism of "inhibition of production, promotion of excretion, and modulation of gut microbiota." Its natural origin and multi-target characteristics hold potential for clinical translation. However, challenges such as low bioavailability and insufficient clinical evidence (lack of large-scale, long-term studies) remain. Future research should focus on: ① developing nano-formulations or combined use with probiotics to improve bioavailability; ② conducting dose optimization studies for different populations; and ③ elucidating the molecular mechanisms of the gut microbiota–uric acid metabolic axis. With advances in formulation technology and mechanistic research, quercetin is expected to become a novel adjuvant therapy for hyperuricemia management.

References 

[1] Shi Y, Williamson G. Quercetin lowers plasma uric acid in pre-hyperuricaemic males: a randomised, double-blinded, placebo-controlled, cross-over trial. Br J Nutr. 2016 Mar 14;115(5):800-6. 

[2] Meng Q, Song C, Ma J, Cui J, Zhan J, Zhao J, Zhang Y, Zhu Z, Du X. Quercetin Prevents Hyperuricemia Associated With Gouty Arthritis by Inactivating the NLRP3/NF-κB Signaling Pathway. Chem Biol Drug Des. 2025 Apr;105(4):e70103. 

[3] Peng B, Dai J, Ji S, Yang Y, Zuo A, Xu S, Fang W, Li D, You Y, Jiang Z, Wu C, Kwan HY, Zhao X, Liu Y. Quercetin ameliorates hyperuricemic nephropathy through improving gut dysfunctions and decreasing gut bacteria-derived uremic toxins. Phytomedicine. 2025 Jul 25;143:156801. 

[4] Bian X, Ge Z, Chen X, Zhong S, Li L, Xu W, Li B, Chen S, Lv G. Protective effects and mechanisms of quercetin in animal models of hyperuricemia: A systematic review and meta-analysis. Pharmacol Res. 2025 Mar;213:107665.