去甲基化酶ALKBH5介导的TREX1 m6A修饰调控cGAS-STING信号通路促进放射性肝损伤的机制

放疗是原发性肝癌的有效治疗方法之一。放疗激活肝脏非实质细胞cGAS-STING-IFNα/β固有免疫信号通路，促进放射诱导肝损伤（RILD），限制放疗效果。另外，放射剂量达到一定阈值也会激活核酸酶TREX1消化过多的双链DNA，抑制cGAS-STING信号通路的活化，但其调控机制并不清楚。我们前期研究发现，肝Kupffer细胞受照射后，会促进m6A去甲基化酶ALKBH5的表达。另外，ALKBH5通过对TREX1 mRNA去甲基化并下调其 mRNA表达。据此，我们提出假说：放疗能通过ALKBH5对TREX1 mRNA去甲基化激活cGAS-STING通路，影响Kupffer细胞的功能以及肝细胞的放射敏感性，进而影响RILD的进展。本项目拟从细胞、动物、临床样本等方面，从cGAS-STING-IFNα/β固有免疫及mRNA m6A甲基化等新角度，揭示RILD的发生机制及提供防治新思路。

Radiotherapy (RT) is one of the mian treatments for primary hepatoceullar carcinoma. Iron irradiation (IR) could trigers cGAS-STING-IFNα/β innate immune signaling pathway and promote radiation-induced liver disease (RILD) by regulating liver non-parenchymal cells, which restricts the radiation deliver. At the same time, IR at some dose activates nuclease TREX1, which digests double-strand DNA (dsDNA), and inhibits the activation of STING pathway. However, how IR regulating TREX1 remains unclear. We previously found that the m6A demethylase ALKBH5 was upregulated in Kupffer cells after IR. Besides, ALKBH5 would regulate TREX1 mRNA demethylation and downregulate TREX1 mRNA and then activate the cGAS-STING signaling pathway. Based on these observation, we hypothesized that ALKBH5 may promote TREX1 mRNA demethylation, then activates the cGAS-STING signaling pathway and influences the function of Kupffer Cells and radiosensitivity of hepatocytes to influence the development of RILD. Our research is intended to use the cell, animal and clinical samples to provide a new prospective from cGAS-STING-IFNα/β innate immune signaling pathway and mRNA m6A methylation to reveal the mechanism and offer a novel preventative and therapeutic strategies for RILD.