Jia Liyang, Sun Boyu, Nie Anzheng, Shi Yamin, Zhou Zheng, Zhu Chunsheng
Department of Traditional Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
The Third People's Hospital of Qingdao, Qingdao 266000, China.
Phytomedicine. 2025 Sep;145:157084. doi: 10.1016/j.phymed.2025.157084. Epub 2025 Jul 16.
The increasing incidence rate of hyperuricemia (HUA), a common chronic metabolic disease, seriously threatens public health. Previous studies have shown that rosmarinic acid (RA) has a good effect in lowering uric acid (UA). However, the exact mechanism of RA in treating HUA is still not fully understood.
To validate the therapeutic effect of RA on HUA and its potential pharmacological mechanisms through a comprehensive analysis of the gut microbiome, metabolomics and molecular interaction techniques.
A rat model of HUA was replicated with 10 % fructose water. The therapeutic effect of RA on HUA rats for 28 consecutive days was assessed through histopathology and biochemical analyses. Additionally, 16S rDNA sequencing, metabolomics, molecular docking, molecular dynamics simulation (MDS), surface plasmon resonance (SPR) and microScale thermophoresis (MST) were used to investigate the mechanisms of RA for HUA treatment.
RA could significantly reduce uric acid (UA) levels, inhibit the activities of UA synthase xanthine oxidase (XOD) and adenosine deaminase (ADA), and improve the function of intestinal and renal tissues. Furthermore, RA altered the composition of the gut microbiota in rats by reducing the Firmicutes to Bacteroidota ratio and increasing the abundance of Bacteroides at the genus level. RA could influence the levels of XOD, ADA, and other plasma metabolites. Importantly, RA modulated ABCG2 expression in the intestine and kidney, as well as URAT1 expression in the kidney. MDS proved that RA bound tightly to these transporters, the SRP results indicated that the equilibrium dissociation constants of RA with GLUT9 is 6.20 μM, RA with URAT1 is 667 nM respectively, and the MST results indicated that the equilibrium dissociation constants of RA and ABCG2 is 264.6 nM.
RA can promote UA excretion by regulating the imbalance of gut microbiota and the expressions of URAT1, GLUT9 and ABCGT2 in HUA rats. This study, for the first time, combined gut microbiota, metabolomics and molecular interaction techniques to verify the intrinsic molecular mechanism of RA in the treatment of HUA, providing a basis for the development of UA-lowering drugs.
高尿酸血症（HUA）作为一种常见的慢性代谢性疾病，其发病率不断上升，严重威胁公众健康。既往研究表明，迷迭香酸（RA）在降低尿酸（UA）方面具有良好效果。然而，RA治疗HUA的确切机制仍未完全明确。
通过综合分析肠道微生物组、代谢组学和分子相互作用技术，验证RA对HUA的治疗效果及其潜在的药理机制。
用10%果糖水复制HUA大鼠模型。通过组织病理学和生化分析评估RA连续28天对HUA大鼠的治疗效果。此外，采用16S rDNA测序、代谢组学、分子对接、分子动力学模拟（MDS）、表面等离子体共振（SPR）和微量热泳动（MST）研究RA治疗HUA的机制。
RA可显著降低尿酸（UA）水平，抑制尿酸合成酶黄嘌呤氧化酶（XOD）和腺苷脱氨酶（ADA）的活性，并改善肠道和肾脏组织功能。此外，RA通过降低厚壁菌门与拟杆菌门的比例并增加拟杆菌属水平的丰度，改变了大鼠肠道微生物群的组成。RA可影响XOD、ADA和其他血浆代谢物的水平。重要的是，RA调节肠道和肾脏中ABCG2的表达以及肾脏中URAT1的表达。MDS证明RA与这些转运蛋白紧密结合，SRP结果表明RA与GLUT9的平衡解离常数为6.20 μM，RA与URAT1的平衡解离常数分别为667 nM，MST结果表明RA与ABCG2的平衡解离常数为264.6 nM。
RA可通过调节HUA大鼠肠道微生物群失衡以及URAT1、GLUT9和ABCGT2的表达促进尿酸排泄。本研究首次结合肠道微生物群、代谢组学和分子相互作用技术，验证了RA治疗HUA的内在分子机制，为开发降尿酸药物提供了依据。
