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<p>The stimulator of interferon genes (STING) pathway serves as a crucial nexus in inflammatory responses and cell death. Despite its role in Mitochondria-Endoplasmic Reticulum Contact (MERC), the mechanistic contributions to inflammatory outcomes remain poorly understood. In clinical acute respiratory distress syndrome (ARDS) models of COVID-19 infection and animal models of LPS-induced acute lung injury (ALI), the STING pathway is closely associated with the pyroptosis pathway. The macrophage STING-N-GSDMD-mtDNA positive feedback loop, upon LPS challenge, induces inflammatory responses and pyroptosis. The GSDMD inhibitor disulfiram (DSF) specifically abrogates the N-terminal portion of GSDMD anchored to the mitochondrial membrane. Furthermore, macrophage STING mediates the direct interaction between Drp1 and N-GSDMD on mitochondrial membrane by regulating mitochondrial calcium, linking mitochondrial fission to the induction of inflammatory responses. Targeting STING-mediated mitochondrial homeostasis, both genetically and pharmacologically, may play a protective role in preventing and treating sepsis-induced acute lung injury. Overall, our study posits that STING deficiency mitigates the cooperative interaction between N-GSDMD and Drp1 in mediating mitochondrial permeabilization and rupture following LPS challenge, paving the way for further investigations into inflammation and pyroptosis.</p> Graphical abstract <p></p>

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Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月8日

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  • Shishi Zou,
  • Yifan Zuo,
  • Yukai Chen,
  • Tianyu Zhang,
  • Tinglv Fu,
  • Guorui Li,
  • Rui Xiong,
  • Bohao Liu,
  • Yong Hu,
  • Zhaoyu Hu,
  • Chunguang Miao,
  • Xiaojing Wu,
  • Ning Li,
  • Qing Geng

摘要

The stimulator of interferon genes (STING) pathway serves as a crucial nexus in inflammatory responses and cell death. Despite its role in Mitochondria-Endoplasmic Reticulum Contact (MERC), the mechanistic contributions to inflammatory outcomes remain poorly understood. In clinical acute respiratory distress syndrome (ARDS) models of COVID-19 infection and animal models of LPS-induced acute lung injury (ALI), the STING pathway is closely associated with the pyroptosis pathway. The macrophage STING-N-GSDMD-mtDNA positive feedback loop, upon LPS challenge, induces inflammatory responses and pyroptosis. The GSDMD inhibitor disulfiram (DSF) specifically abrogates the N-terminal portion of GSDMD anchored to the mitochondrial membrane. Furthermore, macrophage STING mediates the direct interaction between Drp1 and N-GSDMD on mitochondrial membrane by regulating mitochondrial calcium, linking mitochondrial fission to the induction of inflammatory responses. Targeting STING-mediated mitochondrial homeostasis, both genetically and pharmacologically, may play a protective role in preventing and treating sepsis-induced acute lung injury. Overall, our study posits that STING deficiency mitigates the cooperative interaction between N-GSDMD and Drp1 in mediating mitochondrial permeabilization and rupture following LPS challenge, paving the way for further investigations into inflammation and pyroptosis.

Graphical abstract