Hyperoside alleviates zearalenone-induced liver injury by regulating mitochondrial calcium overload mediated...

Zearalenone (ZEA), one of the most common mycotoxins in moldy plants, can cause ferroptosis in the liver. Hyperoside (Hyp) is mainly derived from Hypericum perforatum and exerts hepatoprotective, neuroprotective, and cardioprotective effects. It is not known whether Hyp alleviates ZEA-induced ferroptosis-related damage AIM: The protective effect of Hyp on ZEA-induced liver injury was studied and its underlying mechanisms were elucidated.

The protective effect of Hyp on ZEA-induced liver injury was determined based on ALT and AST levels and by using H&E staining and transmission electron microscopy. The protective effect of Hyp in attenuating ferroptosis was determined by measuring mitophagy- and ferroptosis-related indices. CETSA and siRNA transfection were used to determine the targeting of Hyp to MCU protein.

Hyp attenuated ZEA-induced ferroptosis and excessive mitophagy in hepatocytes, and use of Hyp or FUNDC1 knockdown by siRNA decreased ferroptosis in AML12 cells. Furthermore, Hyp attenuated ZEA exposure-induced Gpx4 interaction with FUNDC1 and reversed the recruitment and degradation of glutathione peroxidase 4 to mitochondria. Hyp was found to target MCU protein to attenuate mitochondrial Ca²⁺ overload and mitophagy induced by upregulated ZEA exposure. MCU knockdown reversed ZEA-induced mitophagy. Hyp also reversed ZEA-induced excessive mitochondrial fission and impairment in mitochondrial function.

Our study demonstrated that Hyp could alleviate ZEA induced ferroptosis by targeting MCU to inhibit mitochondrial Ca²⁺overloaded mitophagy.Our findings provide evidence for Hyp as an effective treatment in alleviating ferroptosis-related liver injury.