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Background <p>Mitochondrial DNA (mtDNA), acting as a critical damage associated molecular pattern (DAMP), can translocate into the cytoplasm and directly activate the cGAS-STING signaling pathway. This activation induces the production of type I interferons and senescence associated secretory phenotype (SASP), positioning mtDNA as a key regulator of both inflammation and cellular senescence, namely mtDNA-cGAS-STING signaling axis. </p> Main text <p>Here, we summarize the molecular mechanisms by which cytoplasmic escape of mtDNA and activation of the cGAS-STING pathway trigger a series of downstream cascade reactions. In addition, we discuss the role of the mtDNA-cGAS-STING axis in various inflammation-related pathologies, including ocular diseases, neurodegenerative disorders, pulmonary inflammation, cardiovascular diseases, and oral diseases. </p> Conclusions <p>Although interventions targeting the mtDNA-cGAS-STING signaling axis have shown promise in preclinical models, challenges regarding specificity, targeted delivery, and potential side effects remain and require further investigation before clinical translation. A deeper mechanistic understanding of the mtDNA-cGAS-STING axis may provide innovative therapeutic strategies for managing inflammation and aging-associated diseases.</p>

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Mitochondrial DNA as a driver of inflammation via the cGAS-STING pathway

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Xingyue Wen,
  • Fan Yang,
  • Lan Zhang,
  • Dingming Huang

摘要

Background

Mitochondrial DNA (mtDNA), acting as a critical damage associated molecular pattern (DAMP), can translocate into the cytoplasm and directly activate the cGAS-STING signaling pathway. This activation induces the production of type I interferons and senescence associated secretory phenotype (SASP), positioning mtDNA as a key regulator of both inflammation and cellular senescence, namely mtDNA-cGAS-STING signaling axis.

Main text

Here, we summarize the molecular mechanisms by which cytoplasmic escape of mtDNA and activation of the cGAS-STING pathway trigger a series of downstream cascade reactions. In addition, we discuss the role of the mtDNA-cGAS-STING axis in various inflammation-related pathologies, including ocular diseases, neurodegenerative disorders, pulmonary inflammation, cardiovascular diseases, and oral diseases.

Conclusions

Although interventions targeting the mtDNA-cGAS-STING signaling axis have shown promise in preclinical models, challenges regarding specificity, targeted delivery, and potential side effects remain and require further investigation before clinical translation. A deeper mechanistic understanding of the mtDNA-cGAS-STING axis may provide innovative therapeutic strategies for managing inflammation and aging-associated diseases.