Interferon-αstimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis  

作　　者：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 

机构地区：[1]National Key Laboratory of Medical Immunology&Institute of Immunology,Naval Medical University,Shanghai,200433,China [2]Department of General Surgery,the First Medical Center of Chinese PLA General Hospital,Beijing,100853,China [3]Translational Medicine Research Center,Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital,Beijing,100853,China [4]Center for Immunotherapy,Chinese Academy of Medical Sciences,Beijing,100005,China

出　　处：《Military Medical Research》2025年第2期184-203,共20页军事医学研究(英文版)

基　　金：National Key Research and Development Program of China(2023YFC2505900);National Natural Science Foundation of China(92269204,82171755,92369106,82171749,82171811,82073184);Military Outstanding Youth Program(2020QN06119,01-SWK JYCJJ07,23SWAQ53);Program of Leading Talents in Shanghai,and Shanghai Shuguang Program(20SG39)。

摘　　要：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-αincreased 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-αstimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA,suggesting the potential clinical application of IFN-αin the prevention of hepatic ferroptosis during liver I/R injury.

关 键 词：Ischemia/reperfusion(I/R) DExH-box helicase 58(DHX58) Glutathione peroxidase 4(GPX4) m6A modification YT521-B homology domain containing 2(YTHDC2) 

分 类 号：R575[医药卫生—消化系统]