| First Author | Jia KW | Year | 2024 |
| Journal | Mil Med Res | Volume | 11 |
| Issue | 1 | Pages | 22 |
| PubMed ID | 38622688 | Mgi Jnum | J:351312 |
| Mgi Id | MGI:7666163 | Doi | 10.1186/s40779-024-00524-9 |
| Citation | Jia KW, et al. (2024) Interferon-alpha stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis. Mil Med Res 11(1):22 |
| abstractText | 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-alpha 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-alpha stimulates DHX58 to promote the translation of m(6)A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-alpha in the prevention of hepatic ferroptosis during liver I/R injury. |
