Lipid Peroxidation in Ferroptosis and Association with Nonalcoholic Fatty Liver Disease

² State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 130022 Changchun, Jilin, China

^*Correspondence: ccguoyan@163.com (Yan Guo); xzyin@ciac.ac.cn (Xunzhe Yin)

Front. Biosci. (Landmark Ed) 2023, 28(12), 332; https://doi.org/10.31083/j.fbl2812332

Submitted: 23 May 2023 | Revised: 28 July 2023 | Accepted: 21 August 2023 | Published: 6 December 2023

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Metabolic Liver Disease-associated Hepatocellular Carcinoma)

This is an open access article under the CC BY 4.0 license.

Abstract

Nonalcoholic fatty liver disease (NAFLD) constitutes a commonly diagnosed liver pathology with perturbed lipid metabolism, which is mainly caused by excessive accumulation of fat in hepatocytes by various pathogenic factors. Currently, there are no effective drug treatments for NAFLD. Ferroptosis represents a novel form of programmed cell death depending on iron, which is driven by large cellular amounts of reactive oxygen species (ROS) and lipid peroxides. Ferroptosis plays critical regulatory roles in the pathogenesis of NAFLD, and overaccumulation of Fe ${}^{2+}$ contributes to lipid peroxidation, which subsequently aggravates NAFLD. Therefore, ferroptosis suppression might constitute an important target for NAFLD treatment. This article reviews the discovery, production pathways, and defense mechanisms of ferroptosis, and explores its association with NAFLD. This may provide new reference targets and strategies for the development of NAFLD drugs from the perspective of ferroptosis.

Keywords

ferroptosis

lipid peroxidation

nonalcoholic fatty liver disease

ferritinophagy

Funding

20210204029YY/Science and Technology Development Plan of Jilin Province

YDZJ202201ZYTS151/Science and Technology Development Plan of Jilin Province

Figures

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Fig. 1.

Pathways of ferroptosis. Ferroptosis can be triggered through inhibiting the system Xc ${}^{-}$ /GSH/GPX4 axis or the accumulation of Fe ${}^{2+}$ and lipid peroxidation. Blocking or inhibiting the Xc ${}^{-}$ /GSH/GPX4 axis can result in decreased intracellular cysteine levels and suppressing the lipid repair function of GPX4. Consequently, disruption of the antioxidant capacity of cells contributes to the initiation and progression of ferroptosis. In lipid metabolism, the most important characteristics of ferroptosis are the increase of intracellular iron ion concentration and the abnormal accumulation of lipid ROS. FSP1 can negatively regulate ferroptosis through CoQ10, thereby inhibiting the delivery of lipid peroxides. Ferritinophagy plays a crucial role in the association between ferritinophagy and ferroptosis. Intracellular ferritin is transported to autophagy lysosomes for degradation, leading to the release of free iron and ultimately triggering ferroptosis. Abbreviations: GPX4, glutathione peroxidase 4; PUFAs, polyunsaturated fatty acids; ACSL4, acyl-CoA synthetase long chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; PL-OO $\cdot{}$ , phospholipid peroxyl radical; TCA, tricarboxylic acid; GSH, glutathione; ROS, reactive oxygen species; FSP1, ferroptosis suppressor protein 1; CoQ10, coenzyme Q10; GCH1, GTP cyclohydrolase 1. ATP, adenosine triphosphate.

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