Abstract

Introduction Sepsis is a leading cause of mortality in critically ill patients, characterized by dysregulation of multiple biological systems, including the complement, coagulation and contact pathways Nafamostat (NM), a serine protease inhibitor, has shown potential in modulating these systems. Objectives We investigated the potential therapeutic role of NM in sepsis and its mechanism. Methods High-throughput mass spectrometry proteomics analysis was conducted to investigate changes in protein levels among sepsis patients. Leveraging the chemical structure of NM, multiple drug-target prediction databases were employed to forecast potential targets. In septic mice, evaluation of complement, coagulation, and contact system activation were conducted after NM administration. Plasma Kininogen 1 (KNG1) was overexpressed to validate roles in the occurrence and development of sepsis. A retrospective study was conducted to evaluate the impact of NM as an anticoagulant for continuous renal replacement therapy (CRRT) on the prognosis of septic patients. Results 107 differentially expressed proteins (DEPs) were identified in sepsis patients with varying prognosis. 622 predicted targets for NM and 184 DEPs in sepsis were identified, with 16 overlapped genes enriching in complement and coagulation cascades. NM reduced plasma KNG1 cleavage and downstream products, alleviating organ damage in septic mice. In a small pilot cohort, NM reduced SOFA scores and platelet consumption while prolonging APTT compared to unfractionated heparin. Conclusion NM may offer a novel therapeutic approach by modulating dysregulated pathways, thus improving organ function and clinical outcomes in sepsis.