Guo Zhiye, Du Xiaolong, Xing Chunlei, Shi Zhiguang, Xu Dandan, Ran Feng, Su Li, Lu Shan
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, China (Z.G., Z.S., D.X., S.L.).
School of Life Sciences and Biotechnology, Institute of Mechanobiology and Medical Engineering, Shanghai Jiao Tong University, China (Z.G.).
Circ Res. 2025 Aug 29;137(6):e157-e174. doi: 10.1161/CIRCRESAHA.125.326540. Epub 2025 Aug 5.
Deep vein thrombosis (DVT), the third most common cause of cardiovascular deaths, is characterized by intravascular clot formation, often accompanied by inflammation. Although the STING (stimulator of interferon genes) signaling pathway is well recognized for its role in mediating inflammation in the context of infection, cellular stress, and tissue, its intricate involvement in DVT remains enigmatic.
In this study, we investigated the role of myeloid cell-intrinsic STING signaling in DVT progression using murine models. Both STING inhibitors and genetic depletion of myeloid-specific STING were used to assess their effects on thrombus formation. In addition, we explored the interaction between STING and YBX1 (Y-box-binding protein 1) through biochemical analyses. A synthetic peptide, C-ST16 (cell penetrating peptide [CPP]-segment), designed to mimic STING inhibitors, was tested for its therapeutic potential in reducing thrombus formation and inflammatory responses.
Our results demonstrate that myeloid cell-intrinsic STING signaling is a key driver in DVT progression. STING inhibition, either through specific inhibitors or genetic depletion of myeloid-specific STING, significantly ameliorated thrombus formation in murine DVT models. Furthermore, we identified a direct interaction between STING and YBX1, resulting in nuclear translocation and heightened thrombotic inflammation. The synthetic peptide, C-ST16, effectively reduced thrombus formation and inflammatory factor expression, without causing hepatorenal toxicity.
These findings highlight the critical role of myeloid-specific STING-YBX1 signaling in driving inflammation during DVT progression. The potential therapeutic use of STING inhibitors, particularly the synthetic peptide C-ST16, presents a promising approach for DVT management, offering novel insights into targeted anti-inflammatory therapies for thrombotic disorders.
深静脉血栓形成（DVT）是心血管死亡的第三大常见原因，其特征是血管内形成血栓，常伴有炎症。尽管干扰素基因刺激物（STING）信号通路在介导感染、细胞应激和组织环境中的炎症方面的作用已得到充分认识，但其在DVT中的复杂参与仍不清楚。
在本研究中，我们使用小鼠模型研究了髓系细胞内源性STING信号在DVT进展中的作用。使用STING抑制剂和髓系特异性STING的基因敲除来评估它们对血栓形成的影响。此外，我们通过生化分析探索了STING与Y盒结合蛋白1（YBX1）之间的相互作用。一种设计用于模拟STING抑制剂的合成肽C-ST16（细胞穿透肽[CPP]片段），测试了其在减少血栓形成和炎症反应方面的治疗潜力。
我们的结果表明，髓系细胞内源性STING信号是DVT进展的关键驱动因素。通过特异性抑制剂或髓系特异性STING的基因敲除抑制STING，可显著改善小鼠DVT模型中的血栓形成。此外，我们发现STING与YBX1之间存在直接相互作用，导致核转位并加剧血栓性炎症。合成肽C-ST16有效减少了血栓形成和炎症因子表达，且未引起肝肾毒性。
这些发现突出了髓系特异性STING-YBX1信号在DVT进展过程中驱动炎症的关键作用。STING抑制剂，特别是合成肽C-ST16的潜在治疗用途，为DVT管理提供了一种有前景的方法，为血栓性疾病的靶向抗炎治疗提供了新的见解。
