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Cited by 529Liver Disease Diagnosis and TreatmentFerroptosis and cancer prognosisLiver physiology and pathology

Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis

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Tsurusaki, Shinya, Tsuchiya, Yuichi, Koumura, Tomoko, Nakasone, Misaki, Sakamoto, Taro, Matsuoka, Masaki, Imai, Hirotaka, Yuet-Yin Kok, Cindy +4 more·2019·Cell Death & Disease
DOI 10.1038/s41419-019-1678-yPMC PMC6579767
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Abstract

Nonalcoholic steatohepatitis (NASH) is a metabolic liver disease that progresses from simple steatosis to the disease state of inflammation and fibrosis. Previous studies suggest that apoptosis and necroptosis may contribute to the pathogenesis of NASH, based on several murine models. However, the mechanisms underlying the transition of simple steatosis to steatohepatitis remain unclear, because it is difficult to identify when and where such cell deaths begin to occur in the pathophysiological process of NASH. In the present study, our aim is to investigate which type of cell death plays a role as the trigger for initiating inflammation in fatty liver. By establishing a simple method of discriminating between apoptosis and necrosis in the liver, we found that necrosis occurred prior to apoptosis at the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model. To further investigate what type of necrosis is involved in the initial necrotic cell death, we examined the effect of necroptosis and ferroptosis inhibition by administering inhibitors to wild-type mice in the CDE diet model. In addition, necroptosis was evaluated using mixed lineage kinase domain-like protein (MLKL) knockout mice, which is lacking in a terminal executor of necroptosis. Consequently, necroptosis inhibition failed to block the onset of necrotic cell death, while ferroptosis inhibition protected hepatocytes from necrotic death almost completely, and suppressed the subsequent infiltration of immune cells and inflammatory reaction. Furthermore, the amount of oxidized phosphatidylethanolamine, which is involved in ferroptosis pathway, was increased in the liver sample of the CDE diet-fed mice. These findings suggest that hepatic ferroptosis plays an important role as the trigger for initiating inflammation in steatohepatitis and may be a therapeutic target for preventing the onset of steatohepatitis.

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  • Hepatocytes begin to die by lytic forms of cell death including necroptosis, pyroptosis and ferroptosis, causing damage to surrounding tissue.

    “Hepatocytes begin to die by lytic forms of cell death including necroptosis(202, 203), pyroptosis(204, 205) and ferroptosis(206), causing damage to surrounding tissue.”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [206]

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Cited by

Sorted by citations

Authors
Tsurusaki, S., Tsuchiya, Y., Koumura, T., Nakasone, M., Sakamoto, T., Matsuoka, M., Imai, H., Yuet-Yin Kok, C., Okochi, H., Nakano, H., Miyajima, A., & Tanaka, M.
Affiliations
  • National Center for Global Health and Medicine (JP)
  • Toho University (JP)
  • Kitasato University (JP)
  • Institute for Quantitative Biosciences, The University of Tokyo (JP)
Corresponding author
Tanaka, Minoru
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2019-06-18
Volume
10
Issue
6
Pages
449-449
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-019-1678-y
PMC
PMC6579767
OpenAlex
W2952112680
Cited by
529
References
5
Citations by year
2026: 70 · 2025: 82 · 2024: 120 · 2023: 85 · 2022: 86 · 2021: 54 · 2020: 31 · 2019: 1
FWCI
34.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • The Japanese Biochemical Society
Funders
  • Japan Agency for Medical Research and Development (JP18gm1210002, JP18gm0910013)
  • MEXT | Japan Society for the Promotion of Science (JP26110007, JP15H01386, JP17H05513, JP26110003, JP26253023)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
nonalcoholic steatohepatitis, ferroptosis, necroptosis, apoptosis, liver inflammation, necrosis, MLKL, choline-deficient ethionine-supplemented diet, hepatocyte death, immune cell infiltration, steatosis
MeSH terms
Necroptosis, Ferroptosis, Animals, Carbon Tetrachloride, Chromans, Diet, Ethionine, Hepatitis, Iron Chelating Agents, Liver, Male, Mice, Inbred C57BL, Necrosis, Cytokines, Apoptosis, Mice, Knockout, Hepatocytes, Mice, Non-alcoholic Fatty Liver Disease

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