1. Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis
- Author
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Kai-Wei Jia, Ren-Qi Yao, Yi-Wen Fan, Ding-Ji Zhang, Ye Zhou, Min-Jun Wang, Li-Yuan Zhang, Yue Dong, Zhi-Xuan Li, Su-Yuan Wang, Mu Wang, Yun-Hui Li, Lu-Xin Zhang, Ting Lei, Liang-Chen Gui, Shan Lu, Ying-Yun Yang, Si-Xian Wang, Yi-Zhi Yu, Yong-Ming Yao, and Jin Hou
- Subjects
Ischemia/reperfusion (I/R) ,DExH-box helicase 58 (DHX58) ,Glutathione peroxidase 4 (GPX4) ,m6A modification ,YT521-B homology domain containing 2 (YTHDC2) ,Medicine (General) ,R5-920 ,Military Science - 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.
- Published
- 2024
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