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  3. A STAT1-GBP3-STING positive feedback loop governs inflammation, oxidative stress, and DNA damage to trigger acute aortic dissection

A STAT1-GBP3-STING positive feedback loop governs inflammation, oxidative stress, and DNA damage to trigger acute aortic dissection

  • Cell Signal. 2025 Nov:135:112015. doi: 10.1016/j.cellsig.2025.112015.
Si-Ming Bu 1,  Wen-Li Wang 2,  Yi-Mei Liu 1,  Qing Li 1,  Jing-Yu Sun 1,  Xu-Rao Zhao 1,  Xu-Bin Miao 1,  Yong-Bo Zhao 3,  Ya-Pei Zhao 4,  Zhi-Xue Song 5,  Dong Ma 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, and Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
  • 2 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, and Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Department of Ultrasound, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050061, China.
  • 3 Cardiac Surgery Department, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 051000, China.
  • 4 Department of Ultrasound, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050061, China.
  • 5 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, and Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, Hebei Medical University, Shijiazhuang, Hebei 050017, China. Electronic address: 18701394@hebmu.edu.cn.
  • 6 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, and Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, Hebei Medical University, Shijiazhuang, Hebei 050017, China. Electronic address: madong119@hebmu.edu.cn.
PMID: 40714274 DOI: 10.1016/j.cellsig.2025.112015
Abstract

Acute aortic dissection (AAD) is a degenerative aortic remodeling disease characterized by exceedingly high mortality without effective pharmacologic therapies. Although oxidative stress, DNA damage, and inflammation are associated with AAD, the precise interplay among these responses has remained unclear. In this study, aortas from mouse AD models were subjected to integrative ATAC-seq and RNA-seq analysis. The pathogenic targets governing oxidative stress, DNA damage, and inflammation were identified by single-cell RNA Sequencing, ROS staining, chromatin immunoprecipitation combined with PCR (ChIP-PCR), and co-immunoprecipitation (CoIP) analysis in the IFN-γ-stimulated vascular smooth muscle cells (VSMCs), mouse AAD model, and human ascending aortas. The transcriptional profiles of 191 differentially expressed genes revealed the IFN-γ response, oxidative stress-related NOD-like Receptor, STING signaling pathways and marked elevation of STAT1, activated inflammation, DNA damage and ROS. Mechanistically, the activation of STAT1 binding on promoters of GBP3, H2aX and IFN-γ gene in nuclear as well as the interaction of GBP3 and STING protein in cytoplasm, determining a STAT1-GBP3-STING positive feedback loop triggering inflammation, DNA damage, and oxidative stress. Targeting this loop using STAT1 Inhibitor Fludarabine impedes aortic degeneration while improving survival (60 % vs. 90 %) and reducing aortic expansion (2.34 ± 0.18 mm vs. 1.55 ± 0.15 mm) in the mouse AAD model. This study provides novel insights into a transcriptional program permitting aortic degeneration, warranting consideration of a critical target STAT1 for an anti-inflammation, anti-DNA damage, and anti-oxidative stress intervention as an attractive strategy to manage temporal-specific AD by modulating the STAT1-GBP3-STING positive feedback loop.

Keywords

Acute aortic dissection; DNA damage; Inflammation; Oxidative stress; STAT1.

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