2. Academic Validation
  3. Blockade of the mitochondrial DNA release ameliorates hepatic ischemia-reperfusion injury through avoiding the activation of cGAS-Sting pathway

Blockade of the mitochondrial DNA release ameliorates hepatic ischemia-reperfusion injury through avoiding the activation of cGAS-Sting pathway

  • J Transl Med. 2024 Aug 28;22(1):796. doi: 10.1186/s12967-024-05588-8.
Yi Xiong # 1,  Jiawen Chen # 1,  Wei Liang # 1,  Kun Li 2,  Yingqi Huang 1,  Jingwen Song 1,  Baoyu Zhang 3,  Xiusheng Qiu 4,  Dongbo Qiu 5,  Qi Zhang 6 7,  Yunfei Qin 8 9
Affiliations

Affiliations

  • 1 Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China.
  • 2 Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China.
  • 3 Neurosurgery Department, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China.
  • 4 Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China.
  • 5 Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China. qiudb3@mail.sysu.edu.cn.
  • 6 Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China. keekee77@126.com.
  • 7 Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China. keekee77@126.com.
  • 8 Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, Guangdong, PR China. qinyf6@mail.sysu.edu.cn.
  • 9 Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat- sen University, Guangzhou, 510630, Guangdong, PR China. qinyf6@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39198913 DOI: 10.1186/s12967-024-05588-8
Abstract

Background: Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated.

Methods: Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models.

Results: Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver Enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization.

Conclusions: The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.

Keywords

Hepatic ischemia-reperfusion injury; Innate immunity; STING; cGAS; mtDNA.

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