Matrine disrupts Nrf2/GPX4 antioxidant system and promotes hepatocyte ferroptosis

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Chemico-Biological Interactions Pub Date : 2023-10-01 DOI:10.1016/j.cbi.2023.110713

Xi Wang, Wenjing Zhu, Miao Xing, Haiyan Zhu, Enqing Chen, Jie Zhou

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Abstract

Matrine (MT) is an alkaloid isolated from Sophora ﬂavescens with various bioactivities and is widely used clinically. However, the broader its clinical use, the greater its toxicity concerns. We investigate the role of ferroptosis in MT-induced liver injury caused by an imbalance in the antioxidant pathway. Our results showed that MT could cause pathological changes in liver tissues and lead to a signiﬁcant reduction in L02 cell viability. MT also reduced superoxide dismutase (SOD) and glutathione (GSH), increased malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation levels, and disrupted iron homeostasis, leading to ferroptosis. In addition, MT decreased the protein levels of FTH, Nrf2, xCT, GPX4, HO-1 and ferroptosis suppressor protein 1 (FSP1) and increased the protein levels of TRF1 and DMT1, characteristic indicators of ferroptosis. Interestingly, the cytotoxic effects of MT were alleviated by ferroptosis inhibitor, Nrf2 agonist, or selenium supplementation. These results revealed that MT triggers hepatocyte ferroptosis by inhibiting the Nrf2/GPX4 antioxidant system.

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苦参碱破坏Nrf2/GPX4抗氧化系统并促进肝细胞脱铁性贫血。

苦参碱（MT）是从苦参中分离出来的一种生物碱，具有多种生物活性，临床应用广泛。然而，其临床应用范围越广，其毒性问题就越大。我们研究了脱铁性贫血在MT诱导的肝损伤中的作用，该损伤是由抗氧化途径失衡引起的。我们的研究结果表明，MT可导致肝组织病理变化，并导致L02细胞活力显著降低。MT还降低了超氧化物歧化酶（SOD）和谷胱甘肽（GSH），增加了丙二醛（MDA）、活性氧（ROS）和脂质过氧化水平，并破坏了铁稳态，导致脱铁症。此外，MT降低了FTH、Nrf2、xCT、GPX4、HO-1和脱铁抑制蛋白1（FSP1）的蛋白水平，并增加了脱铁症的特征指标TRF1和DMT1的蛋白水平。有趣的是，MT的细胞毒性作用通过脱铁抑制剂、Nrf2激动剂或补硒而减轻。这些结果表明MT通过抑制Nrf2/GPX4抗氧化系统触发肝细胞脱铁性贫血。

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

Chemico-Biological Interactions 生物-毒理学

CiteScore

7.70

自引率

3.90%

发文量

410

审稿时长

36 days

期刊介绍： Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.