Parthenolide attenuates sepsis-associated coagulopathy by suppressing NR3C2 in endothelial cells.

OBJECTIVE

To explore the protective effects of parthenolide (PTL) in sepsis-associated coagulopathy (SAC) and its underlying molecular mechanisms.

METHODS

A mouse model of sepsis was generated to evaluate PTL's effects on lung histopathological changes, inflammatory factor expression, and coagulation dysfunction. In HMEC-1 cells, the impact of PTL on lipopolysaccharide (LPS)-induced inflammation, procoagulant state, and apoptosis was analyzed. Bioinformatics analysis was employed to predict PTL's target genes. These predicted targets were cross-referenced with sepsis and coagulation dysfunction-associated genes for key regulators. The expression changes of the key candidate, Nuclear receptor subfamily 3 group C member 2 (NR3C2), were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), and Western blot. Molecular docking analysis was subsequently performed to predict the potential interaction between PTL and NR3C2. Furthermore, an NR3C2 overexpression experiment was conducted to investigate its functional role in the protective effects mediated by PTL.

RESULTS

PTL pretreatment attenuated lung histopathological damage and reduced the levels of inflammatory cytokines and coagulation-related markers, including tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), and thrombin-antithrombin complex (TAT), in septic mice. In HMEC-1 cells, PTL effectively suppressed LPS-induced inflammation, procoagulant activity, and apoptosis. Bioinformatics analysis, corroborated by experimental validation, suggested that NR3C2 might be a key target of PTL. Molecular docking analysis further demonstrated a favorable binding affinity between PTL and NR3C2. NR3C2 overexpression partially reversed the PTL-induced reductions in inflammatory responses and cellular injury, suggesting that NR3C2 may be involved in these effects of PTL.

CONCLUSION

PTL attenuates selected coagulation-related abnormalities and inflammatory injury in experimental sepsis, and these effects may be associated with the regulation of NR3C2 expression. These findings provide preliminary evidence supporting further investigation of PTL and NR3C2 in sepsis-associated coagulopathy (SAC).