Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis

• DOI: 10.1186/s40779-024-00524-9
• Publication Date: 2024-04-15T05:02:04Z
• Authors: 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; Jin Hou
• Keywords: 0301 basic medicine; Medicine (General); U; Glutathione peroxidase 4 (GPX4); Research; Dichlorodiphenyl Dichloroethylene; YT521-B homology domain containing 2 (YTHDC2); Interferon-alpha; Ischemia/reperfusion (I/R); m6A modification; Mice; 03 medical and health sciences; R5-920; Military Science; Reperfusion Injury; Hepatocytes; DExH-box helicase 58 (DHX58); Animals; Ferroptosis; RNA; RNA, Messenger

Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and frequently observed war wounds trauma. Hepatocyte ferroptosis plays a critical role in I/R injury, however, it remains unclear whether this process controlled or regulated members of the DEAD/DExH-box helicase (DDX/DHX) family. The expression DDX/DHX family was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, partial operation performed. Single-cell RNA sequencing (scRNA-seq) post suggested enhanced Dhx58hep-/-. mRNAs proteins associated with DExH-box 58 (DHX58) immunoprecipitation-sequencing (RIP-seq) IP-mass spectrometry (IP-MS). Excessive production reactive oxygen species (ROS) decreased IFN-stimulated gene hepatocytes promoted ferroptosis, while treatment IFN-α increased DHX58 prevented injury. Mechanistically, RNA-binding activity constitutively associates mRNA glutathione peroxidase 4 (GPX4), central suppressor, recruits m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote translation Gpx4 an m6A-dependent manner, thus enhancing GPX4 protein levels preventing ferroptosis. This study provides mechanistic evidence that stimulates m6A-modified mRNA, suggesting potential clinical application prevention