Proteomics Reveals Differential Diagnosis Biomarkers Between Sepsis and Hemophagocytic Syndrome

Background/Objectives: Hemophagocytic Lymphohistiocytosis (HLH) shares many clinical features with sepsis. To improve HLH diagnosis and its differential diagnosis with sepsis, serum proteomic analyses of healthy donors, HLH and septic patients were performed. Methods: Twenty-four individuals were enrolled in a label-free MS/MS spectrometry analysis. STRING was conducted to study the protein-protein interactions overrepresented within the proteins of each comparison. To integrate the functions of the proteins with their respective regulation patterns, Ingenuity Pathway Analysis software was used. Validation of selected proteins was carried out by ELISA. Results: Proteomic results revealed 537 differentially expressed proteins (DEPs) between HLH and sepsis, 471 DEPs between HLH and healthy donors, and 37 DEPs between sepsis and healthy donors. These results were subjected to functional analysis, which showed that apart from inflammation and lipid metabolism, the proteostasis network was deeply impaired in the HLH condition. Considering this information, protein fold changes and the functions of six proteins were validated by ELISA. Conclusions: sCD300a, sCD300b and sCD25 could be specific serum biomarkers for HLH diagnosis, and SAA-1 and LRG1 might be useful biomarkers for differential diagnosis between sepsis and HLH. PSMB1, a non-catalytic subunit of the 20S proteasome, showed promising results for HLH-specific and differential diagnosis. Its elevation in HLH patients may reflect an intensified demand for protein turnover, possibly driven by a higher activation of the immunoproteasome. These insights contribute to expanding our understanding of HLH pathophysiology regarding new pathways and highlight innovative therapeutic interventions, such as Bortezomib and other next-generation inhibitors, designed to modulate immunoproteasome activity.