Matrine disrupts Nrf2/GPX4 antioxidant system and promotes hepatocyte ferroptosis

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

doi:10.1016/j.cbi.2023.110713

Matrine disrupts Nrf2/GPX4 antioxidant system and promotes hepatocyte ferroptosis

Chem Biol Interact. 2023 Oct 1:384:110713. doi: 10.1016/j.cbi.2023.110713. Epub 2023 Sep 15.

Authors

Xi Wang¹, Wenjing Zhu¹, Miao Xing¹, Haiyan Zhu¹, Enqing Chen¹, Jie Zhou²

Affiliations

¹ School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China.
² School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China. Electronic address: zj9032@126.com.

PMID: 37716422
DOI: 10.1016/j.cbi.2023.110713

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.

Keywords: Ferroptosis; GPX4; Hepatotoxicity; Matrine; Nrf2.