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Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis
- Source :
- Military Medical Research, Vol 11, Iss 1, Pp 1-18 (2024)
- Publication Year :
- 2024
- Publisher :
- BMC, 2024.
-
Abstract
- Abstract 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 Dhx58 hep−/− . 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.
Details
- Language :
- English
- ISSN :
- 20549369
- Volume :
- 11
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Military Medical Research
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.9aec556d40f84893b46abef83a3deabd
- Document Type :
- article
- Full Text :
- https://doi.org/10.1186/s40779-024-00524-9