18beta-glycyrrhetinic acid alleviates deoxynivalenol-induced hepatotoxicity by inhibiting GPX4-dependent ferroptosis.

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon Pub Date : 2025-01-09 DOI:10.1016/j.toxicon.2025.108228

Chenchen Song, Wei Wang, Yu Hua, Aimei Liu

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引用次数: 0

Abstract

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.

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18 -甘草次酸通过抑制gpx4依赖性铁下垂减轻脱氧雪腐酚诱导的肝毒性。

脱氧雪腐镰刀菌醇（DON）是一种严重污染农产品的霉菌毒素，可引起肝毒性。铁下垂是一种依赖铁的细胞死亡形式，肝脏是铁积累的重要器官。18 -甘草酸（GA）具有抗铁下垂和保肝作用。本研究旨在探讨GA对don诱导的HepG2细胞和小鼠肝毒性的保护作用。体外实验结果显示，DON （0.4 μM）降低GPX4、SLC7A11、GCLC、NQO1和Nrf2的表达；促进TFR-1表达、MDA、4-HNE和总ROS生成；谷胱甘肽耗竭加速；脂质ROS积累增强和铁（II）超载，导致铁下垂。预处理GA （0.4 μM和6 μM）可逆转这些变化，减轻don诱导的铁下垂，从而提高细胞活力和增殖能力。体内实验结果还显示，GA （10 mg/kg bw）预给药可减轻DON （2 mg/kg bw）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下垂。此外，GA通过促进GPX4和SLC7A11的表达来阻止erastin和rsl3诱导的铁下垂。总之，GA通过激活gpx4依赖性途径阻止铁下垂，从而减轻don诱导的肝毒性。本研究结果为食品真菌毒素毒性的预防提供了理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicon 医学-毒理学

CiteScore

4.80

自引率

10.70%

发文量

358

审稿时长

68 days

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