Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC₅₀ value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage.

高尿酸血症是介导痛风和肾脏损害的主要因素，而黄嘌呤氧化酶（XOD）是高尿酸血症发病的关键酶。在此背景下，设计并合成了一系列栀子苷衍生物，并在体外和体内评估了所有衍生物的抗高尿酸血症和肾脏保护作用。化合物2e成为最有效的 XOD 抑制剂，IC ₅₀值为 6.67 ± 0.46 µM。同时，细胞活力、ROS 生成和 SOD 水平测定表明，化合物2e可以通过抑制氧化应激反应来修复 HKC 细胞的损伤。研究结果表明化合物2e通过抑制 XOD 活性显着降低尿酸水平，并通过抑制 TLR4/TLR2/MyD88/NF-κB 和 NALP3/ASC/caspase-1 信号通路的表达来修复肾脏损伤。酶抑制动力学表明，化合物2E运作经由可逆的混合竞争性抑制。此外，进行了分子对接研究以深入了解化合物2e与 XOD的结合模式。这些结果表明，栀子苷衍生物有可能被开发成一种新型药物，以揭示在自然预防和降低高尿酸血症和肾脏损伤风险方面的健康益处。