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.

暴露于电离辐射 (IR) 后的肝损伤，无论是意外的还是治疗性的，都可能导致肝功能障碍。目前，放疗（RT）被用于各种癌症，包括肝细胞癌（HCC）；然而，治疗剂量受限于高死亡率的放射性肝病（RILD）。此外，RILD 的精确分子机制仍然知之甚少。在这里，我们使用各种经过全肝照射的敲除小鼠品系研究了 RILD 发病机制。我们发现肝细胞在照射后会释放出大量的双链 DNA（dsDNA）。非实质细胞 (NPC) 中的 cGAS-STING 通路被这种 dsDNA 迅速激活，导致干扰素 (IFN)-I 的产生和释放以及伴随的肝细胞损伤。IFN-I 信号通路的遗传和药理学消融保护免受 RILD。此外，临床辐照的人 HCC 周围肝组织表现出比未辐照组织显着更高的 STING 和 IFNβ 表达。放射后血清 IFNβ 浓度增加与患者的 RILD 发展相关。这些结果将 cGAS-STING 诱导的 NPC 中 1 型干扰素释放描述为 IR 诱导的肝损伤的关键介质，并描述了先天免疫驱动的病理学机制，将 cGAS-STING 激活与初始辐射诱导的肝损伤的放大联系起来。放射后血清 IFNβ 浓度增加与患者的 RILD 发展相关。这些结果将 cGAS-STING 诱导的 NPC 中 1 型干扰素释放描述为 IR 诱导的肝损伤的关键介质，并描述了先天免疫驱动的病理学机制，将 cGAS-STING 激活与初始辐射诱导的肝损伤的放大联系起来。放射后血清 IFNβ 浓度增加与患者的 RILD 发展相关。这些结果将 cGAS-STING 诱导的 NPC 中 1 型干扰素释放描述为 IR 诱导的肝损伤的关键介质，并描述了先天免疫驱动的病理学机制，将 cGAS-STING 激活与初始辐射诱导的肝损伤的放大联系起来。