Kong Xiaoran, Zhao Li, Huang He, Kang Qiaozhen, Lu Jike, Zhu Jiaqing
School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Food Laboratory of Zhongyuan, Zhengzhou University, Zhengzhou, 450001, Henan, China.
Food Funct. 2025 Mar 31;16(7):2840-2856. doi: 10.1039/d4fo04867a.
Hyperuricemia is a chronic metabolic disease with high incidence, and it has become a severe health risk in modern times. Isorhamnetin is a natural flavonoid found in a variety of plants, especially fruits such as buckthorn. The hyperuricemia ameliorating effect of isorhamnetin and the specific molecular mechanism were profoundly investigated using a hyperuricemia mouse model in this study. Results indicated that isorhamnetin showed a significant uric acid-lowering effect in mice. Isorhamnetin was able to reduce uric acid production by inhibiting XOD activity. Furthermore, it reduced the expression of GLUT9 to inhibit uric acid reabsorption and enhanced the expression of ABCG2, OAT1, and OAT3 to promote uric acid excretion. Metabolomics analysis revealed that gavage administration of isorhamnetin restored purine metabolism and riboflavin metabolism disorders and thus significantly alleviated hyperuricemia in mice. Furthermore, the alleviating effect of isorhamnetin on hyperuricemia-induced renal inflammation and its specific mechanism were explored through network pharmacology and molecular validation experiments. Network pharmacology predicted that seven targets were enriched in the PI3K/AKT pathway (CDK6, SYK, KDR, RELA, PIK3CG, IGF1R, and MCL1) and four targets were enriched in the NF-κB pathway (SYK, PARP1, PTGS2, and RELA). Western blot analysis validated that isorhamnetin inhibited the phosphorylation of PI3K and AKT and down-regulated the expression of NF-κB p65. It indicated that isorhamnetin could inhibit the PI3K/AKT/NF-κB signaling pathway to reduce the levels of renal inflammatory factors (TNF-α, IL-β and IL-6) and ultimately ameliorate hyperuricemia-induced renal inflammation in mice. This study provides a comprehensive and strong theoretical basis for the application of isorhamnetin in the field of functional foods or dietary supplements to improve hyperuricemia.
高尿酸血症是一种发病率较高的慢性代谢性疾病，在现代已成为严重的健康风险。异鼠李素是一种存在于多种植物中的天然黄酮类化合物，尤其是沙棘等水果中。本研究使用高尿酸血症小鼠模型深入研究了异鼠李素改善高尿酸血症的作用及具体分子机制。结果表明，异鼠李素对小鼠具有显著的降尿酸作用。异鼠李素能够通过抑制黄嘌呤氧化酶（XOD）活性来减少尿酸生成。此外，它降低了葡萄糖转运蛋白9（GLUT9）的表达以抑制尿酸重吸收，并增强了ATP结合盒转运体G2（ABCG2）、有机阴离子转运体1（OAT1）和有机阴离子转运体3（OAT3）的表达以促进尿酸排泄。代谢组学分析显示，灌胃给予异鼠李素可恢复嘌呤代谢和核黄素代谢紊乱，从而显著减轻小鼠的高尿酸血症。此外，通过网络药理学和分子验证实验探讨了异鼠李素对高尿酸血症诱导的肾脏炎症的缓解作用及其具体机制。网络药理学预测，有7个靶点富集于磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）通路（细胞周期蛋白依赖性激酶6（CDK6）、脾酪氨酸激酶（SYK）、血管内皮生长因子受体2（KDR）、信号转导和转录激活因子1（RELA）、磷脂酰肌醇-3激酶γ（PIK3CG）、胰岛素样生长因子1受体（IGF1R）和髓细胞白血病-1（MCL1）），4个靶点富集于核因子κB（NF-κB）通路（SYK、聚（ADP-核糖）聚合酶1（PARP1）、环氧合酶-2（PTGS2）和RELA）。蛋白质免疫印迹分析验证了异鼠李素抑制PI3K和AKT的磷酸化，并下调NF-κB p65的表达。这表明异鼠李素可抑制PI3K/AKT/NF-κB信号通路，以降低肾脏炎症因子（肿瘤坏死因子-α（TNF-α）、白细胞介素-β（IL-β）和白细胞介素-6（IL-6））水平，最终改善小鼠高尿酸血症诱导的肾脏炎症。本研究为异鼠李素在功能性食品或膳食补充剂领域应用以改善高尿酸血症提供了全面而有力的理论依据。
