A dual-track strategy: multi-target, bidirectional modulation of uric acid biosynthesis and renal elimination by natural products—molecular insights
Zhihua Xing, Siyu Sun, Lujie Gao, Yue Xu, Linlin Jiang, Guanghuan Shen, Qiao Zhang, Weina Han, Na Ling, Linlin Cui, Guoyu Li, Yingjie Liu, Qinghai DongAbstract
Hyperuricemia (HUA) arises primarily from increased urate production and an imbalance in extra-renal and renal urate excretion, and is accompanied by oxidative stress, inflammatory activation, and tissue injury. Such a networked pathophysiology constrains the utility of single-target intervention strategies. While currently used single-target urate-lowering agents can effectively reduce serum urate, limitations remain in indication selection, combination therapy, safety, and long-term adherence. Natural bioactive small molecules, characterized by multi-target actions and bidirectional regulation, have emerged as a valuable avenue for the integrated prevention and management of HUA and gout. This review summarizes urate-lowering natural products across multiple structural classes—including triterpenoids, flavonoids, phenolic acids, alkaloids, polyphenols, and anthraquinones—outlining their principal pharmacological mechanisms. In line with an ‘efficacy–developability co-optimization’ concept, we further discuss strategies for subsequent lead optimization of natural-product-derived scaffolds, aiming to support the discovery of novel urate-lowering leads and the development of multi-target anti-gout agents.