DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury

Liver damage upon exposure to ionizing radiation(IR),whether accidental or therapeutic,can contribute to liver dysfunction.Currently,radiotherapy(RT)is used for various cancers including hepatocellular carcinoma(HCC);however,the treatment dose is limited by radiation-induced liver disease(RILD)with a high mortality rate.Furthermore,the precise molecular mechanisms of RILD remain poorly understood.Here,we investigated RILD pathogenesis using various knockout mouse strains subjected to whole-liver irradiation.We found that hepatocytes released a large quantity of double-stranded DNA(dsDNA)after irradiation.The cGAS-STING pathway in non-parenchymal cells(NPCs)was promptly activated by this dsDNA,causing interferon(IFN)-I production and release and concomitant hepatocyte damage.Genetic and pharmacological ablation of the IFN-I signaling pathway protected against RILD.Moreover,clinically irradiated human peri-HCC liver tissues exhibited substantially higher STING and IFNβexpression than non-irradiated tissues.Increased serum IFNβconcentrations post-radiation were associated with RILD development in patients.These results delineate cGAS-STING induced type 1 interferon release in NPCs as a key mediator of IR-induced liver damage and described a mechanism of innate-immunity-driven pathology,linking cGAS-STING activation with amplification of initial radiation-induced liver injury.