2. Academic Validation
  3. Cytosporone B ameliorates hypercoagulability in sepsis by agonizing the Nur77-thrombomodulin pathway

Cytosporone B ameliorates hypercoagulability in sepsis by agonizing the Nur77-thrombomodulin pathway

  • J Thromb Haemost. 2025 Oct 31:S1538-7836(25)00673-7. doi: 10.1016/j.jtha.2025.10.008.
Xin Lu 1,  Linlin Chen 1,  Ye Tu 2,  Xinzhu Liu 3,  Guimei Guo 4,  Zixin Li 1,  Yan Wang 5,  Xin Wei 6,  Zhibin Wang 7
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, School of Anesthesiology, Naval Medical University, Shanghai, China.
  • 2 Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3 Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4 Department of Pediatric Nephrology, Rheumatology and Immunology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 5 School of Pharmacy, Naval Medical University, Shanghai, China. Electronic address: [email protected].
  • 6 Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 7 Department of Critical Care Medicine, School of Anesthesiology, Naval Medical University, Shanghai, China. Electronic address: [email protected].
PMID: 41177456 DOI: 10.1016/j.jtha.2025.10.008
Abstract

Background: Sepsis-induced coagulopathy (SIC) is often a sign of high mortality and poor prognosis in patients with sepsis. Thrombomodulin (TM) plays an important anticoagulant role by activating protein (AP)C.

Objectives: Our previous study has shown that the overexpression of Nur77 upregulates TM expression in human umbilical vein endothelial cells (HUVECs). This study aimed to investigate whether upregulation of Nur77 using cytosporone (Csn)-B could ameliorate SIC.

Methods: A mouse model of SIC was prepared by cecum ligation and puncture (CLP) operation. Five hours after CLP, coagulation-related indicators and histopathologic injury of the liver, lungs, and kidneys were investigated. The effect of Csn-B on the clotting time of HUVECs transfected with Nur77 or TM small-interfering RNA in response to tumor necrosis factor α stimulation was observed. The effects of Csn-B on survival, organ damage, microthrombosis, coagulation factors, TM activated protein C anticoagulant system, fibrinolytic system, and Complement System were observed in vascular endothelial conditional knockout Nur77 mice after CLP.

Results: Sepsis-induced upregulation of Nur77 in vascular endothelial cells. Knockout of Nur77 in vascular endothelium exacerbated organ damage and early coagulation dysfunction in sepsis. Csn-B attenuated the procoagulant response of HUVEC to tumor necrosis factor α stimulation, which is dependent on the activation of Nur77-TM pathway. Furthermore, Csn-B relied on activation of vascular endothelial Nur77 to inhibit the increase of coagulation factors, enhance activation of TM activated protein C, restore fibrinolysis homeostasis, and inhibit C3 and C5 activation to ameliorate hypercoagulability in SIC.

Conclusion: Csn-B improves early coagulopathy in sepsis by increasing endogenous TM through upregulating Nur77 in the vascular endothelium.

Keywords

Nur77; blood coagulation disorders; cytosporone B; sepsis; thrombomodulin.

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