2. Academic Validation
  3. Endothelial Gasdermin D Induces Mitochondrial Damage and Activates the STING Pathway in Lipopolysaccharide-Accelerated Atherosclerosis

Endothelial Gasdermin D Induces Mitochondrial Damage and Activates the STING Pathway in Lipopolysaccharide-Accelerated Atherosclerosis

  • Antioxid Redox Signal. 2025 Sep 29. doi: 10.1177/15230864251380286.
Xiaoyue Song 1 2 3 4 5,  Junqiang Xue 1 2 3 4 5,  Enyong Su 1 2 3 4 5,  Shiyao Xie 6,  Xuelin Cheng 7 8,  Peng Yu 9,  Lili Wei 1 2 3 4 5 10,  Ming Liu 7 11,  Hong Jiang 1 2 3 4 5 11 12
Affiliations

Affiliations

  • 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
  • 2 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 NHC Key Laboratory of Ischemic Heart Diseases, Shanghai, China.
  • 4 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 5 National Clinical Research Center for Interventional Medicine, Shanghai, China.
  • 6 Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 7 Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 8 Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 9 Department of Endocrinology and Metabolism, Fudan Institute of Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 10 Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
  • 11 Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 12 Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
PMID: 41017337 DOI: 10.1177/15230864251380286
Abstract

Aims: Chronic inflammation is a widely acknowledged contributor to the development of atherosclerosis. Gasdermin D (GSDMD) serves as a key executor of Pyroptosis in inflammatory diseases. This study aims to determine the role of endothelial GSDMD in lipopolysaccharide (LPS)-accelerated atherosclerosis and elucidate its underlying molecular mechanisms. Results: GSDMD expression was aberrantly activated in both LPS-accelerated atherosclerotic animal models and oxidized low-density lipoprotein plus LPS-treated endothelial cell models. Compared with the control, endothelial GSDMD deficiency attenuated the atherogenesis progression and vascular endothelial inflammation induced by LPS and protected against the progression of mitochondrial damage, the release of mitochondrial ROS and mitochondrial DNA, and the activation of the stimulator of interferon genes (STING) pathway both in vivo and in vitro. Mechanistically, endothelial GSDMD expression mediates mitochondrial membrane permeabilization and mitochondrial damage-associated molecular patterns release and triggers the STING pathway to aggravate atherosclerotic progression. In addition, the STING pathway activation was proved to partially reverse the effects of endothelial GSDMD deficiency both in vivo and in vitro. Moreover, the signal transducer and activator of transcription 3 was identified as a positive regulator of GSDMD expression. Innovation and Conclusion: Our findings elucidate the mechanism by which endothelial GSDMD exerts its atherogenic effects by increasing mitochondrial damage and upregulating the STING pathway in LPS-accelerated atherosclerosis. GSDMD promises to be a critical therapeutic target for atherosclerotic cardiovascular diseases. Antioxid. Redox Signal. 00, 000-000.

Keywords

GSDMD; STING pathway; atherosclerosis; endothelial cell; mitochondrial damage.

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