Abstract

Zearalenone (ZEN) is a mycotoxin that induces hepatic oxidative injury by promoting ROS accumulation and compromising antioxidant defenses. Transcriptomic profiling revealed xanthine oxidase (XOD) as a key mediator. Structure-based molecular docking identified polydatin (PD) from Polygonum cuspidatum as a potent XOD inhibitor with strong binding affinity. Biochemical assays confirmed PD’s XOD inhibition. In vitro and in vivo studies demonstrated that PD significantly attenuated ZEN-induced oxidative stress, reduced ROS generation, and improved pathological markers of liver injury, with optimal efficacy at low concentrations. Molecular dynamics simulations revealed PD forms a stable complex with XOD. Concurrently, PD activated the Nrf2/HO-1 pathway, enhancing SOD and GSH-Px expression while reducing lipid peroxidation. These findings demonstrate that PD mitigates ZEN hepatotoxicity through dual mechanisms: direct XOD inhibition and enhancement of endogenous antioxidant capacity, supporting its therapeutic potential.