Cited by 344Ferroptosis and cancer prognosisLiver Disease Diagnosis and TreatmentIron Metabolism and Disorders

Ferroptosis Affects the Progression of Nonalcoholic Steatohepatitis via the Modulation of Lipid Peroxidation–Mediated Cell Death in Mice

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Qi, Jing, Kim, Jong-Won, Zhou, Zixiong, Lim, Chae-Woong, Kim, Bumseok·2020·The American Journal of Pathology

Abstract

Oxidative stress and its associated lipid peroxidation play a key role in nonalcoholic steatohepatitis (NASH). Ferroptosis is a recently recognized type of cell death characterized by an iron-dependent and lipid peroxidation-mediated nonapoptotic cell death. We demonstrate the impact of ferroptosis on the progression of NASH induced by methionine/choline-deficient diet (MCD) feeding for 10 days. RSL-3 (a ferroptosis inducer) treatment showed decreased hepatic expression of glutathione peroxidase 4 (GPX4) and conversely increased 12/15-lipoxygenase, and apoptosis-inducing factor, indicating that ferroptosis plays a key role in NASH-related lipid peroxidation and its associated cell death. Consistently, levels of serum biochemical, hepatic steatosis, inflammation, and apoptosis in MCD-fed mice were exacerbated with RSL-3 treatment. However, MCD-fed mice treated with sodium selenite (a GPX4 activator) showed increase of hepatic GPX4, accompanied by reduced NASH severity. To chelate iron, deferoxamine mesylate salt was used. Administration of deferoxamine mesylate salt significantly reduced NASH severity and abolished the harmful effects of RSL-3 in MCD-fed mice. Finally, treatment with liproxstatin-1 (a ferroptosis inhibitor) repressed hepatic lipid peroxidation and its associated cell death, resulting in decreased NASH severity. Consistent with the in vivo findings, modulation of ferroptosis/GPX4 affected hepatocellular death in palmitic acid-induced in vitro NASH milieu. We conclude that GPX4 and its related ferroptosis might play a major role in the development of NASH.

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Crossref · 10.1016/j.ajpath.2019.09.011

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Authors
Qi, J., Kim, J.-W., Zhou, Z., Lim, C.-W., & Kim, B.
Affiliations
Jeonbuk National University (KR)
Corresponding author
Kim, Bumseok
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2020-01
Volume
190
Issue
1
Pages
68-81
ISSN
0002-9440 (ISSN-L)
OpenAlex
W2979641493
Cited by
338
References
42
Citations by year
2026: 34 · 2025: 59 · 2024: 78 · 2023: 71 · 2022: 53 · 2021: 24 · 2020: 18
FWCI
17.45
Type
journal article
Language
en
Update notices
erratum (2020-03-01)
Open access
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • China Scholarship Council (201708260022)
  • Ministry of Education (2017R1D1A3B03030521, 2019R1A6A1A03033084)
  • National Research Foundation of Korea
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Keywords
ferroptosis, nonalcoholic steatohepatitis, lipid peroxidation, GPX4, methionine-choline-deficient diet, sodium selenite, deferoxamine, liproxstatin-1, 12/15-lipoxygenase, apoptosis-inducing factor, hepatic steatosis, hepatocyte death, iron chelation
MeSH terms
Ferroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Choline Deficiency, Diet, Inflammation, Male, Methionine, Mice, Inbred C57BL, Lipid Peroxidation, Cell Death, Apoptosis, Oxidative Stress, Disease Progression, Mice, Non-alcoholic Fatty Liver Disease

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