Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis
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 $ m^{6} $A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an $ m^{6} $A-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 $ m^{6} $A-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. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jia, Kai-Wei [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
A modification |
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| Anmerkungen: |
© The Author(s) 2024 |
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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): |
SPR055533108 |
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| 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. 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 $ m^{6} $A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an $ m^{6} $A-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 $ m^{6} $A-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 Ischemia/reperfusion (I/R) |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a DExH-box helicase 58 (DHX58) |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Yao, Ren-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Yi-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ding-Ji |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Min-Jun |e verfasserin |4 aut | |
| 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 | |
| 700 | 1 | |a Li, Yun-Hui |e verfasserin |4 aut | |
| 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 |0 (orcid)0000-0002-8670-517X |4 aut | |
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