A Review of the Anti-Hyperuricemic Effects and Mechanisms of the Natural Product Rutin

Hyperuricemia is a metabolic disorder resulting from purine metabolism disturbances or impaired uric acid excretion. Elevated serum uric acid levels not only trigger gout but are also closely linked to various complications, including renal damage and cardiovascular diseases. Rutin, a flavonoid widely found in plants, has been shown in recent studies to hold significant potential in regulating uric acid metabolism and mitigating hyperuricemia-related injuries. This review summarizes the natural sources and physicochemical properties of rutin, systematically expounds its anti-hyperuricemic mechanisms and relevant research evidence, and analyzes its application value and future research directions. It aims to provide a reference for in-depth studies on the role of rutin in the prevention and adjunctive treatment of hyperuricemia.

Keywords: Rutin; Anti-hyperuricemia; Uric acid metabolism; Xanthine oxidase; Gout

1. Introduction

Hyperuricemia is a metabolic disorder caused by excessive uric acid production or reduced excretion, characterized by abnormally elevated uric acid levels in the blood. It is closely associated with the pathogenesis of various conditions, including gout, kidney disease, and cardiovascular disease. In recent years, with changes in dietary patterns and lifestyles, the incidence of hyperuricemia has been increasing annually, making the prevention and control situation increasingly challenging. Developing safe and effective anti-hyperuricemic interventions is of great significance for preventing and treating related diseases and improving patients' health outcomes. Among numerous natural bioactive components, rutin – a flavonoid widely distributed in plants – has attracted attention due to its extensive sources, favorable safety profile, and multiple biological activities. Recent studies have revealed that rutin not only exerts significant effects in antioxidation, anti-inflammation, and cardiovascular protection but also shows considerable potential in regulating uric acid metabolism and lowering uric acid levels. It exerts anti-hyperuricemic activity through multiple mechanisms of action, thus emerging as a research hotspot in this field.

2. Natural Sources and Physicochemical Properties of Rutin

Rutin, also known as vitamin P, is a flavonol compound. With multiple phenolic hydroxyl groups and glycosidic bonds in its molecular structure, it exhibits diverse biological activities. In nature, rutin shows a distinct plant preference in distribution. Among them, Sophora japonica buds (dried flower buds of the Fabaceae plant Sophora japonica) are its primary source, with rutin content reaching up to 20%-25%. They also serve as the core raw material for large-scale extraction currently. Secondary sources include stems and leaves of Polygonaceae buckwheat, fruits of Rosaceae hawthorn, and peels of Rutaceae citrus. These plants contain a certain amount of rutin, but the content is usually less than 5%, so they only act as auxiliary extraction sources. The physicochemical properties of rutin significantly affect its application. It has poor water solubility, with a solubility of only 0.01g/100mL at room temperature, thus requiring techniques like β-cyclodextrin inclusion and nano-formulation to improve its solubility. It has moderate thermal stability: when processed below 100℃, the activity retention rate can exceed 80%. However, prolonged heating at high temperatures above 120℃ will lead to structural damage and a significant reduction in activity. Additionally, rutin possesses certain antioxidant properties; its phenolic hydroxyl groups can scavenge free radicals, a characteristic closely associated with its synergistic effect in anti-hyperuricemia.

3. Analysis of Multifactorial Etiologies of Hyperuricemia

The core of hyperuricemia lies in excessive production or reduced excretion of serum uric acid, with its etiologies falling into two main categories: endogenous metabolic abnormalities and exogenous environmental factors. In terms of endogenous metabolic disorders, abnormal purine metabolism is a key driver. Xanthine oxidase (XOD), a critical enzyme in uric acid synthesis, exhibits excessive activity that leads to massive conversion of hypoxanthine and xanthine into uric acid. Additionally, genetic factors are noteworthy: genetic variations in uric acid transporters (e.g., URAT1, GLUT9) can enhance renal reabsorption of uric acid while reducing its excretion, which represents the primary cause of familial hyperuricemia. Exogenous environmental factors also impact serum uric acid levels. Regarding dietary patterns, long-term intake of high-purine foods (such as animal offal, seafood, and alcohol) results in excessive exogenous purine intake, increasing the burden of uric acid production. In terms of lifestyle, physical inactivity and obesity reduce metabolic efficiency, slowing uric acid excretion. Furthermore, long-term use of drugs like diuretics and aspirin may inhibit uric acid excretion, thereby inducing hyperuricemia. When the combined effect of these factors causes serum uric acid levels to exceed 420μmol/L (the saturation concentration), urate crystals tend to deposit in tissues such as joints and kidneys, triggering conditions including gouty arthritis, kidney stones, and chronic kidney injury.

4. Core Mechanisms of Rutin's Anti-Hyperuricemic Activity

4.1  Inhibiting uric acid production: targeting xanthine oxidase

The key step in uric acid synthesis is the conversion of xanthine to uric acid, catalyzed by XOD. Rutin can competitively bind to the active site of XOD, thereby inhibiting its catalytic activity and reducing endogenous uric acid production. In vitro experiments have demonstrated that the half-maximal inhibitory concentration (IC50) of rutin against XOD is 12.5μmol/L, which is comparable to that of the clinical drug allopurinol (IC50=8.3μmol/L), with lower toxicity to normal cells.

4.2 Promoting uric acid excretion: regulating renal transporters

The kidney is the primary organ responsible for uric acid excretion. Rutin enhances net uric acid excretion by downregulating the expression of uric acid reabsorption transporters (URAT1, GLUT9) in the renal proximal tubules, while simultaneously upregulating the activity of excretory transporters. Studies have shown that in hyperuricemic rat models, rutin intervention increases renal uric acid excretion rate by 30%-40%, accompanied by a significant reduction in serum uric acid levels.

4.3 Alleviating inflammatory damage: inhibiting inflammatory signaling pathways

Hyperuricemia is often accompanied by urate crystal-induced inflammatory responses (e.g., gouty arthritis). Rutin can reduce the release of inflammatory cytokines (IL-1β, TNF-α, IL-6) by inhibiting the NF-κB signaling pathway, thereby alleviating inflammatory infiltration and tissue damage in joint synovium.

4.4 Antagonizing oxidative stress: improving oxidative damage

Elevated uric acid induces the production of large amounts of reactive oxygen species (ROS) in the body, triggering oxidative stress. The phenolic hydroxyl groups of rutin can directly scavenge ROS; meanwhile, it enhances the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and reduces the level of lipid peroxidation product (MDA). Studies have shown that rutin can restore oxidative stress indices in hyperuricemic model animals to over 80% of normal levels.

4.5 Improving renal function

Chronic hyperuricemia can lead to urate crystal deposition in the kidneys, causing renal interstitial fibrosis and impairing renal excretory function. Rutin exerts certain renal protective effects: it reduces urate deposition in the kidneys, inhibits the expression of transforming growth factor-β1 (TGF-β1), and alleviates renal interstitial fibrosis. Additionally, rutin mitigates renal inflammation and oxidative stress damage induced by hyperuricemia, improves renal filtration function, and thereby promotes uric acid excretion.

5.  Anti-Hyperuricemic Evidence and Therapeutic Potential of Rutin

5.1 Preclinical and Preliminary Clinical Evidence

In preclinical and preliminary clinical studies, rutin has demonstrated certain anti-hyperuricemic activity. For animal experiments, a total of 12 studies have confirmed that rutin (50-200 mg/kg) can reduce serum uric acid levels in hyperuricemic model animals by 20%-40%, with a better safety profile than chemical drugs. Cell experiments have shown that rutin inhibits XOD activity in a concentration-dependent manner and promotes uric acid excretion in renal tubular cells. In preliminary clinical observations, a trial involving 30 patients with mild hyperuricemia indicated that daily intake of 300 mg rutin extract reduced serum uric acid levels from 450 μmol/L to 390 μmol/L after 8 weeks, with no significant adverse reactions. However, due to the small sample size, the results require further validation.

5.2 Applications and Future Perspectives

Rutin holds certain application value in the field of anti-hyperuricemia, with its development directions focusing on three aspects:

First, the development of health products. Leveraging its advantages of natural origin and safety, it can be developed into dietary supplements for populations with hyperuricemia (e.g., rutin chewable tablets, effervescent tablets) or compounded with probiotics into functional foods to assist in lowering uric acid. Second, optimization of formulation technologies. To address rutin’s poor water solubility, technologies such as nanoemulsions and microencapsulation can improve its bioavailability. Existing studies have shown that the uric acid-lowering effect of nanonized rutin can be enhanced by 2-3 times. Third, exploration of combined applications. The synergistic effects between rutin and other natural components such as quercetin and curcumin remain unclear; exploring combined formulations is expected to enhance anti-hyperuricemic efficacy.

6. Safety Evaluation of Rutin

Existing studies have demonstrated that rutin exhibits favorable safety within conventional dosage ranges. Animal studies have shown that its median lethal dose (LD50) exceeds 5000 mg/kg, and no significant organ damage or toxic reactions were observed in subchronic toxicity studies (90 days). In clinical studies, common adverse reactions are mild gastrointestinal discomfort, such as nausea and abdominal distension; diarrhea may occur with high-dose administration, but symptoms resolve spontaneously upon discontinuation. In vitro genotoxicity tests yielded negative results, with no mutagenic effects detected. Currently, rutin has been widely used in food additives and health supplements, though the safety of long-term high-dose administration requires further clinical research for confirmation.

7. Rutin in Anti-Hyperuricemic Products and Health Management

Rutin, with its significant anti-hyperuricemic activity, has broad application prospects in the fields of medicine, health products, and food. In the pharmaceutical field, rutin can be developed into anti-hyperuricemic drugs for the treatment of gout and hyperuricemia. It can also be used in combination with other anti-hyperuricemic drugs to enhance efficacy and reduce adverse reactions. In the health product sector, rutin can be formulated into capsules, tablets, and other dosage forms as health supplements for auxiliary uric acid reduction, suitable for high-risk groups of hyperuricemia and patients in the remission stage of gout. In the food field, rutin can be added to functional foods such as beverages and pastries to help people regulate uric acid levels through daily diet and prevent the occurrence of hyperuricemia. In addition, some natural foods rich in rutin, such as buckwheat and sophora flowers, can also be chosen as healthy dietary options for daily health management of people with hyperuricemia.

8. Conclusion and Future Directions

As a natural flavonoid, rutin exhibits notable anti-hyperuricemic activity and a favorable safety profile. Its mechanisms of action primarily include inhibiting uric acid production and promoting uric acid excretion, along with associated anti-inflammatory and antioxidant effects, which have been widely validated in cellular and animal models. Currently, the application of rutin in anti-hyperuricemic products has made some progress; however, clinical trial data in humans remain relatively limited. Further research is still needed to clarify its specific efficacy and dosage requirements in the human body. Future research directions should focus on further investigating the molecular mechanisms underlying rutin’s anti-hyperuricemic activity, optimizing its formulation processes to enhance bioavailability, and conducting more large-scale, long-term clinical trials in humans. These efforts will provide more robust scientific evidence for the widespread application of rutin in the field of anti-hyperuricemia. With the advancement of research, rutin is expected to emerge as a safe and effective anti-hyperuricemic intervention, making significant contributions to the prevention and treatment of hyperuricemia and related diseases.

References

[1] Wu H, Wang Y, Huang J, et al. Rutin ameliorates gout via reducing XOD activity, inhibiting ROS production and NLRP3 inflammasome activation in quail[J]. Biomedicine & Pharmacotherapy, 2023, 158: 114175.

[2] Yu Y, Xiong Y, Tong S, et al. Inhibitory Activity of Quercetin, Rutin, and Hyperoside against Xanthine Oxidase: Kinetics, Fluorescence, and Molecular Docking[J]. Current Pharmaceutical Biotechnology, 2025, 26(4): 513-524.

[3] Li K, Wang Y, Liu W, et al. Structure–activity relationships and changes in the inhibition of xanthine oxidase by polyphenols: A review[J]. Foods, 2024, 13(15): 2365.

[4] Ullah Z, Yue P, Mao G, et al. A comprehensive review on recent xanthine oxidase inhibitors of dietary based bioactive substances for the treatment of hyperuricemia and gout: Molecular mechanisms and perspective[J]. International Journal of Biological Macromolecules, 2024, 278: 134832.

[5] Du L, Zong Y, Li H, et al. Hyperuricemia and its related diseases: mechanisms and advances in therapy[J]. Signal Transduction and Targeted Therapy, 2024, 9(1): 212.

[6] Adachi S, Oyama M, Kondo S, et al. Comparative effects of quercetin, luteolin, apigenin and their related polyphenols on uric acid production in cultured hepatocytes and suppression of purine bodies‐induced hyperuricemia by rutin in mice[J]. Cytotechnology, 2021, 73(3): 343-351.