High-throughput mass spectrometry proteomics and bioinformatics analysis identify Nafamostat as a potential therapeutic agent for sepsis. Animal experiments suggest that Nafamostat may intervene in sepsis by targeting the complement, coagulation, and contact systems. • Through proteomic analysis and enrichment analysis of plasma from sepsis patients with varying prognoses, we identified differentially expressed proteins (DEPs) and highlighted key pathways. Network pharmacology highlighted NM as a compelling candidate for further exploration. • In a murine model of sepsis, the administration of NM significantly improved multi-organ dysfunction. NM inhibited the overactivation of the complement, contact and coagulation systems during the early stages of sepsis. • NM enhanced vital signs and clinical outcomes in sepsis patients receiving continuous renal replacement therapy. • These findings suggest that NM may offer a novel therapeutic strategy for improving organ function and clinical outcomes in sepsis through the modulation of complement and coagulation pathways 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. We investigated the potential therapeutic role of NM in sepsis and its mechanism. 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. 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. NM may offer a novel therapeutic approach by modulating dysregulated pathways, thus improving organ function and clinical outcomes in sepsis.
He et al. (Wed,) studied this question.