Key role of interferon regulatory factor 1(IRF-1)in regulating liver disease:progress and outlook

Interferon regulatory factor 1(IRF-1)is a member of the IRF family.It is the first transcription factor to be identified that could bind to the interferon-stimulated response element(ISRE)on the target gene and displays crucial roles in the interferoninduced signals and pathways.IRF-1,as an important medium,has all of the advantages of full cell cycle regulation,cell death signaling transduction,and reinforcing immune surveillance,which are well documented.Current studies indicate that IRF-1 is of vital importance to the occurrence and evolution of multifarious liver diseases,including but not limited to inhibiting the replication of the hepatitis virus(A/B/C/E),alleviating the progression of liver fibrosis,and aggravating hepatic ischemiareperfusion injury(HIRI).The tumor suppression of IRF-1 is related to the clinical characteristics of liver cancer patients,which makes it a potential indicator for predicting the prognosis and recurrence of liver cancer;additionally,the latest studies have revealed other effects of IRF-1 such as protection against alcoholic/non-alcoholic fatty liver disease(AFLD/NAFLD),cholangiocarcinoma suppression,and uncommon traits in other liver diseases that had previously received little attention.Intriguingly,several compounds and drugs have featured a protective function in specific liver disease models in which there is significant involvement of the IRF-1 signal.In this paper,we hope to propose a prospective research basis upon which to help decipher translational medicine applications of IRF-1 in liver disease treatment.

Chaperone-and PTM-mediated activation of IRF1 tames radiation-induced cell death and the inflammatory response

The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics,but the underlying mechanism remains poorly understood.Here,we revealed that the transcriptional activation of interferon regulatory factor 1(IRF1)in response to ionizing radiation,cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells.Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1,enabling it to regulate the transcription of inflammation-and cell death-related genes.Novel posttranslational modification(PTM)sites in the nuclear localization sequence(NLS)of IRF1 were identified.Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation.Mechanistically,reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1,which restrains radiation-induced and STING/p300-mediated PTMs of IRF1,was revealed.In addition,genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death,and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1.Thus,we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.