Research Progress on Apigenin in Regulating Uric Acid Metabolism

With changes in people's lifestyles and dietary structures, the incidence of hyperuricemia is increasing year by year, becoming a significant threat to human health. Apigenin, a natural flavonoid compound widely present in various plants, has made considerable progress in research on lowering uric acid in recent years. This article reviews the mechanism of action, related experimental studies, and clinical application prospects of apigenin in reducing uric acid, aiming to provide a reference for its further research and application in the prevention and treatment of hyperuricemia and gout.

Keywords: Apigenin; hyperuricemia; uric acid metabolism; antioxidant; anti-inflammatory

1. Introduction

Uric acid is the end product of purine metabolism. An imbalance between its production and excretion leads to hyperuricemia, which can further trigger gout and various chronic diseases. Although clinical drugs for hyperuricemia have certain therapeutic effects, they have varying degrees of side effects. For example, allopurinol may cause severe allergic reactions, and benzbromarone has potential damage to the liver. In contrast, apigenin, a natural flavonoid compound, has become an important direction in uric acid-lowering research due to its safety and wide sources.

2. Biological Basis for Maintaining Uric Acid Homeostasis

The maintenance of uric acid homeostasis relies on the coordinated regulation of multiple organ systems, mainly reflected in three aspects: at the metabolic level, xanthine oxidase, as a key rate-limiting enzyme, regulates uric acid production, and the liver finely adjusts this process through the purine nucleotide metabolic pathway; the kidneys achieve dynamic balance of uric acid excretion through the reabsorption and secretion of urate transporters, among which the transport system of proximal tubular epithelial cells plays a core role; in terms of systemic regulation, insulin resistance reduces uric acid excretion by affecting renal tubular function, and intestinal flora participates in systemic uric acid balance by decomposing approximately 30% of uric acid. These mechanisms are interconnected through a complex feedback regulatory network. When the rate of uric acid production (about 750mg/day) is imbalanced with excretion capacity and exceeds the blood saturation level (6.8mg/dL), hyperuricemia occurs. The molecular basis for maintaining this balance involves precise regulation of multiple signaling pathways.

3. Physicochemical Properties and Biological Metabolism of Apigenin

Apigenin is a flavonoid compound widely found in vegetables and fruits, with a typical phenolic hydroxyl structure and conjugated system, showing weak acidity and moderate lipophilicity. Its water solubility improves significantly with increasing pH. After oral administration, apigenin releases active ingredients through the hydrolysis of its glycoside precursors by intestinal β-glucosidase, and is absorbed through passive diffusion and transporter-mediated processes, with a significant first-pass effect. In the liver, it is catalyzed by enzymes to form sulfated and glucuronidated metabolites, which are secreted into bile and urine through specific transporters, with a plasma half-life of approximately 3-5 hours. Its unique enterohepatic circulation characteristic enables it to release active ingredients again in the intestine, and this multi-stage metabolic feature is closely related to its continuous biological activity in the body.

4. Pathways of Apigenin in Regulating Uric Acid Metabolism

4.1 Inhibiting Uric Acid Production

Xanthine oxidase (XOD) is a key enzyme in the process of uric acid production, which can catalyze the oxidation of hypoxanthine to xanthine and further oxidize xanthine to uric acid. Relevant studies have tested the inhibitory effect of apigenin on xanthine oxidase activity and found that its inhibitory effect is dose-dependent, that is, within a certain range, as the concentration of apigenin increases, the inhibitory effect on xanthine oxidase activity becomes stronger. Compared with allopurinol, a commonly used clinical drug for inhibiting uric acid production, apigenin may be slightly weaker in inhibitory strength, but due to its natural plant origin, it has lower toxic and side effects and certain advantages in terms of safety.

4.2 Promoting Uric Acid Excretion

As the core organ for regulating uric acid homeostasis in the body, the kidneys achieve precise regulation of uric acid excretion through their urate transport system. Apigenin can promote uric acid excretion by bidirectionally regulating renal transporters: on one hand, it inhibits the expression of the uric acid reabsorption protein URAT1, reducing the reabsorption of uric acid into the blood; on the other hand, it enhances the activity of the excretion protein OAT1, helping more uric acid to be excreted through urine. Animal experiments have confirmed that this dual effect can effectively reduce blood uric acid levels, providing a natural solution for hyperuricemia.

4.3 Anti-Inflammatory Effect Assisting in Uric Acid Reduction

Clinical observations show that patients with hyperuricemia generally have a state of low-grade chronic inflammation, which forms a positive feedback regulation of uric acid metabolism disorder by affecting the function of urate transporters and the level of oxidative stress. Apigenin can inhibit the core inflammatory pathway, effectively reduce the levels of key inflammatory factors, and alleviate the interference of inflammation on uric acid metabolism. This anti-inflammatory effect can not only relieve joint symptoms during acute gout attacks but also synergize with its direct uric acid-lowering mechanisms (inhibiting production + promoting excretion), forming dual protection for gout prevention and treatment, and achieving comprehensive intervention from symptom relief to root cause regulation.

5. Clinical Verification of Uric Acid-Lowering Efficacy of Apigenin

Apigenin has shown good uric acid-lowering effects in cell and animal experiments. Studies have found that it can reduce uric acid-absorbing transporters in the kidneys, increase uric acid-excreting transporters, and inhibit the activity of key enzymes for uric acid production in the liver, thereby reducing intracellular uric acid levels. In addition, apigenin can not only effectively reduce blood uric acid levels in hyperuricemia mice but also alleviate kidney damage caused by excessive uric acid. A study involving 109 subjects found that daily intake of 200 grams of fresh celery for 4 weeks could reduce the average blood uric acid by 23.5μmol/L; another study showed that daily consumption of 150 grams of celery for 30 days reduced uric acid levels by 8-12%. These findings provide a scientific basis for apigenin as a potential natural uric acid-lowering ingredient.

6. Biological Safety Evaluation and Potential Health Benefits of Apigenin

As a natural flavonoid compound, apigenin has been confirmed by multiple studies to have good biological safety. No obvious toxicity or severe adverse reactions have been observed under conventional doses, showing broad prospects for health applications. Apigenin not only has excellent antioxidant, anti-inflammatory, and metabolic regulatory effects but also can effectively reduce uric acid levels through multi-target mechanisms, including inhibiting xanthine oxidase activity, regulating the expression of urate transporters, and promoting uric acid excretion. In addition, its potential anti-tumor, neuroprotective, and cardiovascular protective effects have also attracted widespread attention. Appropriate intake of apigenin supplements or foods rich in apigenin shows good tolerance and can significantly improve metabolic indicators in patients with hyperuricemia. These characteristics make apigenin a natural active ingredient with great development value, having important application potential in the fields of functional foods and preventive medicine.

7. Conclusion

As a typical natural plant flavonoid, apigenin has shown various potentials in anti-uric acid research. It regulates uric acid metabolism by inhibiting uric acid production, promoting uric acid excretion, and exerting anti-inflammatory effects, achieving good results in cell and animal experiments. Some clinical studies have also initially shown its benefits for patients with hyperuricemia. With the continuous progress of research technology and in-depth research, apigenin is expected to become a safe and effective anti-uric acid substance, providing new options and ideas for the prevention and treatment of hyperuricemia and related diseases, and playing an important role in the medical and health fields in the future.

References

[1] Salehi B, Venditti A, Sharifi-Rad M, et al. The Therapeutic Potential of Apigenin[J]. Int J Mol Sci, 2019, 20(6): 1305.

[2] Singh D, Gupta M, Sarwat M, et al. Apigenin in cancer prevention and therapy: A systematic review and meta-analysis of animal models[J]. Crit Rev Oncol Hematol, 2022, 176: 103751.

[3] Shen Z, Xu L, Wu T, et al. Structural basis for urate recognition and apigenin inhibition of human GLUT9[J]. Nat Commun, 2024, 15(1): 5039.

[4] Liu T, Gao H, Zhang Y, et al. Apigenin Ameliorates Hyperuricemia and Renal Injury through Regulation of Uric Acid Metabolism and JAK2/STAT3 Signaling Pathway[J]. Pharmaceuticals (Basel), 2022, 15(11): 1442.

[5] Hsu SJ, Chung HC, Chang CH, et al. Rapid evaluation of apigenin bioavailability and hypouricemic bioactivity by targeted metabolomics study in enterohepatic microenvironment mimetic cell culture model[J]. Food Res Int, 2025, 209: 116281.