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

ABSTRACT: 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 IFNβ expression than non-irradiated tissues. Increased serum IFNβ concentrations 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.

SUBMITTER: Du S

PROVIDER: S-EPMC8245603 | biostudies-literature |

REPOSITORIES: biostudies-literature

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| S-EPMC8423402 | biostudies-literature

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