Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation

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Abstract

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI can further develop into serious liver diseases such as cirrhosis and liver cancer. Therefore, how to effectively prevent and treat ALI has become the focus of research. Numerous studies have reported Maresin1 (MaR1) has anti-inflammatory effect and protective functions on organs. In the present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) to establish an ALI model, explored the mechanism of liver cells death caused by D-GalN/LPS, and determined the effect of MaR1 on D-GalN/LPS-induced ALI. In vivo experiments, we found that MaR1 and ferrostatin-1 significantly alleviated D-GalN/LPS-induced ALI, reduced serum alanine transaminase and aspartate transaminase levels, and improved the survival rate of mice. Meanwhile, MaR1 inhibited hepatocyte death, inhibited tissue reactive oxygen species (ROS) expression, reduced malondialdehyde (MDA), reduced glutathione (GSH), GSH/oxidized glutathione (GSSG), and iron content induced by D-GalN/LPS in mice. In addition, MaR1 inhibited ferroptosis-induced liver injury through inhibiting the release of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6. Subsequently, western blot showed that MaR1 improved the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). In vitro experiments, we found that MaR1 inhibited LPS-induced and erastin-induced cell viability reduction. Meanwhile, we found that MaR1 increased the MDA and GSH levels in cells. Western blot showed that MaR1 increased the expression level of Nrf2/HO-1/GPX4. Next, the Nrf2 was knocked down in HepG2 cells, and the results showed that the protective effect of MaR1 significantly decreased. Finally, flow cytometry revealed that MaR1 inhibited ROS production and apoptosis. Overall, our study showed MaR1 inhibited ferroptosis-induced liver injury by inhibiting ROS production and Nrf2/HO-1/GPX4 activation.

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Ferroptosis: mechanisms, biology and role in disease

Xuejun Jiang, Brent Stockwell, Marcus Conrad (2021)

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

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The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis

Kirill Bersuker, Joseph Hendricks, Zhipeng Li … (2019)

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids 1,2 . The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols 3,4 . Ferroptosis has been implicated in the cell death that underlies several degenerative conditions 2 , and induction of ferroptosis by inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death 5 . However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines 6 , suggesting that additional factors govern resistance to ferroptosis. Here, employing a synthetic lethal CRISPR/Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ), generating a lipophilic radical-trapping antioxidant (RTA) that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumor xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a new ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutics.

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Author and article information

Contributors

Ruidong Li: URI : https://loop.frontiersin.org/people/1194186/overview

Kaixiong Tao: URI : https://loop.frontiersin.org/people/1452274/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 04 April 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 865689

Affiliations

[1] ¹ Department of Gastrointestinal Surgery , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan, China

[2] ² Department of Critical Care Medicine , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan, China

Author notes

Edited by: Thomas Brzozowski, Jagiellonian University Medical College, Poland

Reviewed by: Li Zhang, Chongqing Medical University, China

Yuzhen Wang, Inner Mongolia Agricultural University, China

Jingxin Mao, Southwest University, China

Yousef A. Bin Jardan, King Saud University, Saudi Arabia

Toshiaki Ohara, Okayama University, Japan

Lina Chen, Xi’an Jiaotong University Health Science Center, China

Zhiquan Hu, Huazhong University of Science and Technology, China

Jessica Zuñiga-Hernandez, University of Talca, Chile

*Correspondence: Kaixiong Tao, kaixiongtao@ 123456hust.edu.cn ; Ruidong Li, liruidong@ 123456hust.edu.cn

[ † ]

These authors have contributed equally to this work

This article was submitted to Gastrointestinal and Hepatic Pharmacology, a section of the journal Frontiers in Pharmacology

Article

Publisher ID: 865689

DOI: 10.3389/fphar.2022.865689

PMC ID: 9013935

PubMed ID: 35444546

SO-VID: a4f5a1c6-96b7-4c67-ab5c-6d963c6f37b6

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 30 January 2022

Date accepted : 14 March 2022

Funding

Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;

Award ID: 81701883 81874184 82172171

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Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation

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Most cited references 57

Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Ferroptosis: mechanisms, biology and role in disease

The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis

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Cited by 36

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