What question did this study set out to answer?

This research aims to identify protective genes involved in the transition from SIRS to sepsis and elucidate their regulatory pathways.

April 1, 2026Open Access

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

Key Points

This research aims to identify protective genes involved in the transition from SIRS to sepsis and elucidate their regulatory pathways.
Analyzed RNA-sequencing data from patients with sepsis and SIRS.
Used differential expression and weighted gene co-expression network analysis to identify candidate genes.
Conducted functional enrichment and validated findings across clinical cohorts.
Utilized single-cell RNA sequencing and SCENIC analysis to explore cell-specific expression.
Screened Traditional Chinese medicine monomers for potential modulators.
CTSS and NRG1 identified as candidate protective genes, downregulated in sepsis.
Both genes consistently validated across various GEO datasets.
Single-cell analysis highlighted CTSS localization in monocytes and NRG1 enrichment in this cell type.
In vitro studies showed downregulation of both genes in LPS-stimulated macrophages.
Certain TCM monomers predicted to upregulate CTSS and NRG1 expression.

Abstract

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: CTSS and NRG1 were identified as candidate protective genes in the transition from SIRS to sepsis. Both were significantly downregulated in sepsis and consistently validated across GEO datasets. SCENIC analysis suggested that these genes were associated with immune-related transcriptional regulatory networks. Single-cell analysis indicated predominant localization of CTSS in monocytes, while NRG1 showed relative enrichment within this cell population. In vitro, both genes were downregulated in LPS-stimulated macrophages. Several TCM monomers were predicted to upregulate their expression. Conclusion: Integrated transcriptomic, single-cell, and machine learning analyses identified CTSS and NRG1 as potential protective biomarkers in the progression from SIRS to sepsis. Their immune-cell expression patterns, regulatory associations, and possible pharmacologic modulators provide new clues for understanding sepsis pathogenesis and developing therapeutic strategies. Keywords: systemic inflammatory response syndrome, SIRS, sepsis, CTSS, NRG1, SCENIC

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