Song Chenchen, Wang Wei, Hua Yu, Liu Aimei
School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning Hubei 437100, China.
School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China; Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
Toxicon. 2025 Feb;255:108228. doi: 10.1016/j.toxicon.2025.108228. Epub 2025 Jan 9.
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.
脱氧雪腐镰刀菌烯醇（DON）是一种严重污染农产品的霉菌毒素，可导致肝毒性。铁死亡是一种铁依赖性的细胞死亡形式，而肝脏是铁蓄积的重要器官。18β-甘草次酸（GA）具有抗铁死亡和肝脏保护作用。本研究旨在探讨铁死亡在GA对DON诱导的HepG2细胞和小鼠肝毒性保护作用中的作用。体外实验结果显示，DON（0.4 μM）降低了GPX4、SLC7A11、GCLC、NQO1和Nrf2的表达；促进了TFR-1的表达以及MDA、4-HNE和总ROS的产生；加速了谷胱甘肽（GSH）的消耗；增强了脂质ROS的积累和Fe（II）过载，从而导致铁死亡。用GA（0.4和6 μM）预处理可逆转这些变化，减轻DON诱导的铁死亡，从而提高细胞活力和增殖能力。体内实验结果还表明，预先给予GA（10 mg/kg体重）可减轻DON（2 mg/kg体重）诱导的小鼠肝损伤，部分原因是通过减少线粒体损伤和脂质过氧化来抑制铁死亡。此外，GA通过促进GPX4和SLC7A11的表达来预防erastin和RSL3诱导的铁死亡。总之，GA通过激活GPX4依赖性途径预防铁死亡，从而减轻DON诱导的肝毒性。本研究结果为预防食品霉菌毒素毒性提供了理论依据。
