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. 2025 Jul 29:16:1474808.
doi: 10.3389/fendo.2025.1474808. eCollection 2025.

Therapeutic effect and mechanism of gigantol on hyperuricemia

Yuanfan Wu #  1 , Xia Sun #  2 , Yuhan Jia #  3 , Tianshu Gao #  3 , Jin Xu  4 , Youqiao Qian  5 , Naiqi Pei  6 , Lilin Wang  7 , Qiaohong Zheng  6 , Honglei Li  8 , Zhen Chen  3 , Yijiao Liu  3 , Yang Ma  3 , Hui Chen  7 , Yuanyuan Ye  3 , Jiaxin Zhao  3 , Yi Zhou  3 , Xiaoqing Chen  3 , Baosheng Huang  9 , Yefeng Liu  10 , Yin Zhu  11 , Ning Xue  12 , Juan Zhang  13 , Guangfeng Ji  13 , Xing Wang  3
Affiliations

Therapeutic effect and mechanism of gigantol on hyperuricemia

Yuanfan Wu et al. Front Endocrinol (Lausanne). .

Abstract

This study aimed to evaluate the therapeutic effects of gigantol on hyperuricemia (HUA) and investigate the underlying mechanism of HUA. A mouse model of HUA was made by gavage of potassium oxonate, and HK-2 and AML12 cell models were made by adenosine and xanthine oxidase (XOD) induction. We tested the levels of uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), cellular UA, and XOD activity. The levels of NOD-like receptor thermal protein domain 3 (NLRP3) and other inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA) kits. XOD is a protein related to the NLRP3 pathway and also serves as an UA transporter. We found that the levels of UA, CRE, and BUN increased in serum but decreased in urine in HUA model mice. After gigantol treatment, UA, CRE, and BUN levels in serum decreased, whereas their levels in urine increased. The levels of NLRP3 and interleukin-1β (IL-1β) were lower and the expression of NLRP3-related protein decreased after gigantol treatment. In conclusion, gigantol exhibits a therapeutic effect on HUA, and the mechanism may be related to inhibiting XOD activity to reduce UA production, regulating the expression of UA transporters to increase UA excretion, and inhibiting the activation of NLRP3 inflammatory signaling.

Keywords: HUA; NLRP3; UA transporters; gigantol; xanthine oxidase inhibitor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Construction and analysis of the HUA–gigantol PPI network.
Figure 2
Figure 2
GO function analysis of gigantol core targets (A). KEGG pathway enrichment analysis of gigantol core targets (B).
Figure 3
Figure 3
Therapeutic effects of gigantol on HUA models in vivo and in vitro. Effects of gigantol on serum UA (A) serum CRE (B) serum BUN (C) urine UA (D) urine CRE (E) and urine BUN (F) in HUA mice and UA levels in HK-2 (G) and AML12 (H) cells. Data were expressed as mean ± SEM; in (A–C) n = 8, in (D–H) n = 6. Compared with the control group, # p < 0.05, ## p < 0.01, ### p < 0.001. Compared with the model group, * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 4
Figure 4
Effect of gigantol on XOD in vivo and in vitro models of HUA. Gigantol reduced XOD activity in mice liver (A) and AML12 cells (B). Inhibition of protein expression of XOD in HUA mice liver (C, E) and AML12 cells (D, F). Data were expressed as mean ± SEM; in (A), n = 8; in (B), n = 6; in (E) and (F), n = 3. Compared with the control group, ## p < 0.01, ### p < 0.001. Compared with the model group, * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 5
Figure 5
Effects of gigantol on the NLRP3 inflammatory signaling pathway. Gigantol decreased NLRP3 and IL-1β levels in serum (A, B), kidney (C, D), and HK-2 cells (E, F). Gigantol decreased the expression of ASC, caspase-1, and NLRP3 in the kidney of HUA mice (G–J) and HK-2 cells (K–N). Data are expressed as mean ± SEM; in (A–D), n = 8; in (E, F), n = 6; in (G–N), n = 3. Compared with the control group, # p < 0.05, ## p < 0.01, ### p < 0.001. Compared with the model group, * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 6
Figure 6
Effects of gigantol on TNF-α and IL-6 levels in HUA mice serum (A, B), kidney (C, D), and HK-2 cells (E, F). Data were expressed as mean ± SEM; in (A, B), n = 8; in (C–F), n = 6. Compared with the control group, ### p < 0.001. Compared with the model group, * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 7
Figure 7
Effect of gigantol on UA transporters in in vivo and in vitro models of HUA. Gigantol inhibited GLUT9 protein expression and upregulated OAT1 and OAT3 protein expression in HUA mice (A–D) and HK-2 cells (E–H). Data were expressed as mean ± SEM; n = 3. Compared with the control group, # p < 0.05, ## p < 0.01, ### p < 0.001. Compared with the model group, * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 8
Figure 8
Effect of gigantol on pathological changes of liver tissue in mice with HUA (HE, 200×). (A) Blank control group. (B) Model control group. (C) Allopurinol group, 10 mg/kg. (D) Gigantol group, 5 mg/kg. (E) Gigantol group, 10 mg/kg. (F) Gigantol group, 20 mg/kg.
Figure 9
Figure 9
Effect of gigantol on pathological changes of renal tissue in mice with HUA (HE, 200×). (A) Blank control group. (B) Model control group. (C) Allopurinol group, 10 mg/kg. (D) Gigantol group, 5 mg/kg. (E): Gigantol group, 10 mg/kg. (F) Gigantol group, 20 mg/kg.
Figure 10
Figure 10
Blood concentration–time curves of gigantol in rats after intravenous (A) and gavage (B) administration.
Figure 11
Figure 11
Blood concentration–time curves of allopurinol in rats after intravenous (A) and gavage administration (B).
Figure 12
Figure 12
Molecular docking of febuxostat with XOD (A), gigantol with XOD (B), allopurinol with XOD (C), gigantol with GLUT9 (D), OAT1 (E), OAT3 (F), and NLRP3 (G).
Figure 13
Figure 13
Translation implications and clinical development of gigantol.
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