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 interferon(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 N6-methyladenosine(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.