Ferroptosis Affects the Progression of Nonalcoholic Steatohepatitis via the Modulation of Lipid Peroxidation–Mediated Cell Death in Mice
Open accessAbstract
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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The results indicate a possible interplay between ferroptosis and inflammation.
“The results indicate a possible interplay between ferroptosis and inflammation.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [257]
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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
- bronze
- doi.org
- Licence
- 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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