Plasma Proteomic Signatures of Pediatric Sepsis Reveal Persistent Inflammation and Phase‐Specific Biomarkers

ABSTRACT Sepsis remains a leading cause of pediatric morbidity and mortality, yet its molecular underpinnings are poorly understood. Here, we performed mass spectrometry–based plasma proteomics and cytokine profiling in pediatric sepsis patients at the acute phase (AP) and recovery phase (RP), alongside preoperative surgical controls. In AP vs. control, we identified 41 differentially abundant (DA) proteins, including acute‐phase reactants and complement factors, with persistent but attenuated expression in RP. Pathway analysis revealed sustained enrichment in inflammatory and complement activation processes during both AP and RP, with partial restoration of immune surveillance and vascular homeostasis in recovery. Machine learning highlighted complement components (C9, C1R) and LRG1 as candidate AP biomarkers, and S100A9 as an RP‐associated marker. Comparative analysis with adult sepsis proteomes uncovered age‐specific complement activation patterns: adults displayed higher classical pathway activity, whereas pediatric patients exhibited enhanced alternative pathway activity. Cytokine profiling confirmed sustained immune activation and endothelial perturbation across sepsis phases. We also compared the sepsis cohort with the sterile inflammation (SI) cohort, which revealed distinct adaptive immune enrichment in sepsis while innate immune predominance in SI, enabling the identification of potential sepsis‐specific protein signatures. Together, these findings delineate the dynamic immune and vascular proteomic landscape of pediatric sepsis, reveal biomarkers distinguishing sepsis from sterile inflammation, and highlight age‐related complement pathway differences with potential therapeutic implications. Trial Registration: ClinicalTrials.gov : NCT04103268, NCT04299828