Deoxynivalenol (DON), a mycotoxin that severely contaminates agri-food products can cause hepatotoxicity. Ferroptosis is an iron-dependent form of cell death, and the liver is an important organ for iron accumulation. 18beta-glycyrrhetinic acid (GA) has anti-ferroptosis and hepatoprotective effects. This study aimed to investigate the role of ferroptosis in the protective effects of GA against DON-induced hepatotoxicity in HepG2 cells and mice. The in vitro results revealed that DON (0.4 μM) decreased GPX4, SLC7A11, GCLC, NQO1, and Nrf2 expression
promoted TFR-1 expression and MDA, 4-HNE, and total ROS production
accelerated GSH depletion
and enhanced lipid ROS accumulation and Fe(II) overload, leading to ferroptosis. Pre-treatment with GA (0.4 and 6 μM) reversed these changes and alleviated DON-induced ferroptosis, thereby increasing cell viability and proliferation. In vivo results also showed that GA (10 mg/kg bw) pre-administration attenuated DON (2 mg/kg bw)-induced mouse liver injury, in part by inhibiting ferroptosis through reducing mitochondrial damage and lipid peroxidation. In addition, GA prevented erastin- and RSL3-induced ferroptosis by promoting GPX4 and SLC7A11 expression. Altogether, GA attenuated DON-induced hepatotoxicity by preventing ferroptosis via activation of GPX4-dependent pathway. The findings of this study provide a theoretical basis for the prevention of food mycotoxin toxicity.