Myeloid-Specific STING-YBX1 Interaction Alleviates Coagulation in Deep Vein Thrombosis.

Abstract

BACKGROUND 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. METHODS 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, designed to mimic STING inhibitors, was tested for its therapeutic potential in reducing thrombus formation and inflammatory responses. RESULTS 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. CONCLUSIONS 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.