Protective Gene Signatures in the Transition from SIRS to Sepsis: Insights from Integrative Transcriptomics and Validation Across Clinical Cohorts.

Background: The molecular mechanisms underlying the transition from systemic inflammatory response syndrome (SIRS) to sepsis remain unclear. Identifying protective genes and their regulatory pathways may improve understanding of sepsis progression and reveal potential therapeutic targets. Methods: Peripheral blood RNA-sequencing data from 29 patients with sepsis and 11 with SIRS were analyzed. Differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were used to identify candidate genes associated with disease progression. Functional enrichment analyses were then performed. Core genes were selected using LASSO and support vector machine recursive feature elimination (SVM-RFE), and further validated by survival and meta-analyses across GEO cohorts. Single-cell RNA sequencing, combined with SCENIC analysis, was used to characterize cell-specific expression patterns and regulatory networks. An LPS-induced RAW264.7 macrophage model was used for in vitro validation. Traditional Chinese medicine (TCM) monomers were also screened for compounds potentially upregulating core genes. Results: Conclusion: Integrated transcriptomic, single-cell, and machine learning analyses identified