Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis
© 2024. The Author(s)..
BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family.
METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS).
RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis.
CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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Enthalten in: |
Military Medical Research - 11(2024), 1 vom: 15. Apr., Seite 22 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Jia, Kai-Wei [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 17.04.2024 Date Revised 25.04.2024 published: Electronic Citation Status MEDLINE |
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doi: |
10.1186/s40779-024-00524-9 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM37111814X |
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245 | 1 | 0 | |a Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis |
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520 | |a © 2024. The Author(s). | ||
520 | |a BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family | ||
520 | |a METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS) | ||
520 | |a RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis | ||
520 | |a CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury | ||
650 | 4 | |a Journal Article | |
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700 | 1 | |a Zhang, Li-Yuan |e verfasserin |4 aut | |
700 | 1 | |a Dong, Yue |e verfasserin |4 aut | |
700 | 1 | |a Li, Zhi-Xuan |e verfasserin |4 aut | |
700 | 1 | |a Wang, Su-Yuan |e verfasserin |4 aut | |
700 | 1 | |a Wang, Mu |e verfasserin |4 aut | |
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700 | 1 | |a Zhang, Lu-Xin |e verfasserin |4 aut | |
700 | 1 | |a Lei, Ting |e verfasserin |4 aut | |
700 | 1 | |a Gui, Liang-Chen |e verfasserin |4 aut | |
700 | 1 | |a Lu, Shan |e verfasserin |4 aut | |
700 | 1 | |a Yang, Ying-Yun |e verfasserin |4 aut | |
700 | 1 | |a Wang, Si-Xian |e verfasserin |4 aut | |
700 | 1 | |a Yu, Yi-Zhi |e verfasserin |4 aut | |
700 | 1 | |a Yao, Yong-Ming |e verfasserin |4 aut | |
700 | 1 | |a Hou, Jin |e verfasserin |4 aut | |
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