Cyanidin-3-glucoside mitigates zearalenone-enhanced hepatic lipotoxicity via inhibition of PXR activation.

Zearalenone (ZEA) is a mycotoxin frequently detected in food. Cyanidin-3-glucoside (C3G), an anthocyanin abundant in food, exhibits regulatory effects on hepatic metabolism; however, its role in ZEA-induced hepatic lipotoxicity remains unclear. In this study, C57BL/6 J mice were exposed to low-dose ZEA (0.5 mg/kg·bw) combined with a combined with a high-fat diet (HFD) for 96 days, and HepG2 and HepaRG cells were treated with ZEA and oleic acid to investigate chronic ZEA-induced metabolic disturbances. C3G was administered to evaluate its protective effects. ZEA disrupted hepatic energy metabolism, promoted lipid accumulation, and induced more severe lipotoxicity. Mechanistically, ZEA activated the pregnane X receptor (PXR), upregulating fatty acid transporters CD36 and FABP4, thereby enhancing fatty acid uptake and lipid synthesis. C3G inhibits ZEA-induced PXR activation, thereby suppressing PXR signaling and alleviating ZEA-induced hepatic lipotoxicity under HFD conditions. Collectively, C3G mitigates ZEA-induced hepatic lipotoxicity by inhibiting PXR activation, highlighting anthocyanins as potential interventions against mycotoxin-associated metabolic injury.