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<p>Radiation-induced pulmonary fibrosis (RIPF) is a severe complication of thoracic radiotherapy with limited effective treatment options. Cellular senescence has emerged as a critical driver of age-related tissue fibrosis; however, its role in RIPF and potential as a therapeutic target are underexplored. In this study, we investigated whether emodin, a natural compound with known anti-aging properties, alleviates RIPF by suppressing radiation-induced cellular senescence. In a mouse model exposed to 16&#xa0;Gy thoracic irradiation, emodin treatment significantly attenuated pulmonary fibrosis, reduced collagen deposition, and downregulated fibrotic markers. Notably, emodin markedly suppressed radiation-induced senescence in pulmonary epithelial cells, accompanied by reduced secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, emodin preserved mitochondrial integrity, curbed mitochondrial reactive oxygen species (mtROS) accumulation, and prevented mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cGAS-STING-NF-κB signaling pathway, a key pro-inflammatory axis in senescent cells. Importantly, knockdown of cGAS or treatment with the mitochondrial uncoupler CCCP attenuated the anti-senescent effects of emodin, underscoring the centrality of mitochondrial dysfunction and the mtDNA-cGAS-STING axis in senescence-driven fibrosis. Collectively, these findings identify emodin as a novel senescence-targeting agent that mitigates RIPF by alleviating mitochondrial dysfunction and disrupting the mtDNA-cGAS-STING pathway, highlighting its therapeutic potential in age-related fibrotic diseases.</p> Graphical Abstract <p>During the progression of RIPF, ionizing radiation induces mitochondrial dysfunction in pulmonary epithelial cells, characterized by the accumulation of mtROS, loss of mitochondrial membrane potential, and subsequent leakage of mtDNA into the cytoplasm. The cytosolic mtDNA is recognized by cGAS, leading to activation of the STING-NF-κB signaling pathway. This cascade drives cellular senescence and promotes the release of SASP factors, including IL-6, TNF-α, TGF-β, and MMP9. These SASP factors act in a paracrine manner to induce fibroblast-to-myofibroblast transformation, upregulate the expression of α-SMA and Collagen I, and ultimately result in excessive extracellular matrix deposition and pulmonary fibrosis.</p> <p></p>

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Emodin alleviates radiation-induced pulmonary fibrosis by targeting cellular senescence via the mtDNA-cGAS-STING axis

  • 期刊论文

  • 发表日期：

    2026年7月6日

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  • Wei Duan,
  • Yanling Sha,
  • Xi Tang,
  • Riu Liu,
  • Bin Su,
  • Meijing Huang,
  • Xin Xun,
  • Yunfei Ye

摘要

Radiation-induced pulmonary fibrosis (RIPF) is a severe complication of thoracic radiotherapy with limited effective treatment options. Cellular senescence has emerged as a critical driver of age-related tissue fibrosis; however, its role in RIPF and potential as a therapeutic target are underexplored. In this study, we investigated whether emodin, a natural compound with known anti-aging properties, alleviates RIPF by suppressing radiation-induced cellular senescence. In a mouse model exposed to 16 Gy thoracic irradiation, emodin treatment significantly attenuated pulmonary fibrosis, reduced collagen deposition, and downregulated fibrotic markers. Notably, emodin markedly suppressed radiation-induced senescence in pulmonary epithelial cells, accompanied by reduced secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, emodin preserved mitochondrial integrity, curbed mitochondrial reactive oxygen species (mtROS) accumulation, and prevented mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cGAS-STING-NF-κB signaling pathway, a key pro-inflammatory axis in senescent cells. Importantly, knockdown of cGAS or treatment with the mitochondrial uncoupler CCCP attenuated the anti-senescent effects of emodin, underscoring the centrality of mitochondrial dysfunction and the mtDNA-cGAS-STING axis in senescence-driven fibrosis. Collectively, these findings identify emodin as a novel senescence-targeting agent that mitigates RIPF by alleviating mitochondrial dysfunction and disrupting the mtDNA-cGAS-STING pathway, highlighting its therapeutic potential in age-related fibrotic diseases.

Graphical Abstract

During the progression of RIPF, ionizing radiation induces mitochondrial dysfunction in pulmonary epithelial cells, characterized by the accumulation of mtROS, loss of mitochondrial membrane potential, and subsequent leakage of mtDNA into the cytoplasm. The cytosolic mtDNA is recognized by cGAS, leading to activation of the STING-NF-κB signaling pathway. This cascade drives cellular senescence and promotes the release of SASP factors, including IL-6, TNF-α, TGF-β, and MMP9. These SASP factors act in a paracrine manner to induce fibroblast-to-myofibroblast transformation, upregulate the expression of α-SMA and Collagen I, and ultimately result in excessive extracellular matrix deposition and pulmonary fibrosis.