August 15, 2025Open Access

Multi-Omics Analysis Identifies Immune Regulatory Networks in Sepsis-Associated Liver Injury: Experimental Validation and Clinical Relevance

Key Points

T cell-related biomarkers were identified, offering potential therapeutic targets in sepsis-induced liver injury.
Analysis indicated a significant elevation in IL-1β and lactate levels, confirming inflammatory processes during sepsis.
Assessment involved murine models and bioinformatics, integrating functional enrichment and protein interaction networks for insights.
Findings underscore the immune regulatory networks and cytokine interactions, advancing understanding of sepsis-related liver dysfunction.

Abstract

Sepsis-induced liver injury (SILI) significantly contributes to mortality, yet its underlying immune mechanisms remain poorly understood. This study aimed to identify key immune-related genes (IRGs) driving T cell-mediated responses in SILI and evaluate their diagnostic potential. Cecal ligation and puncture (CLP) was performed to establish a murine sepsis model (n=7/group), with sham-operated controls. Serum IL-1β and lactate levels were quantified via ELISA. Public transcriptomic datasets (GSE26440, GSE26378, GSE25504, GSE28750; 180 sepsis vs 53 controls) were analyzed to identify differentially expressed IRGs (DEIRGs). Functional enrichment (GO/KEGG), protein-protein interaction (PPI) networks, and single-cell RNA sequencing (scRNA-seq) were integrated to prioritize T cell-associated genes. Flow cytometry assessed immune cell subsets (CD3+ T cells, CD19+ B cells, NK1.1+ NK cells, F4/80+ macrophages) in murine blood. Liver histopathology (HE staining) and cytokine expression (IL-1β/TNF-α; IHC) were evaluated. CLP mice exhibited elevated IL-1β (P<0.01) and lactate (P<0.01), confirming metabolic dysfunction and inflammation. Bioinformatics analysis identified 19 DEIRGs, with PPI networks implicating immune regulation (PPI enrichment p=3.35×10-6). Flow cytometry confirmed T cell dominance (65.87% vs 63.85% in controls). scRNA-seq revealed four T cell-linked hub genes (FCER1G, IL2RB, PTGDR, XCL1). Protein-protein interaction (PPI) network analysis demonstrated that these genes form a synergistic regulatory network involving NF-κB, JAK-STAT, and other key pathways, with notable features including the IL2RB-XCL1 positive feedback loop and the opposing effects of PTGDR isoforms (DP1/DP2). Histopathology showed hepatic necrosis and inflammatory infiltration, correlating with upregulated IL-1β/TNF-α (IHC, P<0.05). FCER1G, IL2RB, PTGDR, and XCL1 are novel T cell-related biomarkers of SILI, offering potential therapeutic targets. The study bridges bioinformatics predictions with experimental validation, advancing understanding of immune dysregulation in sepsis.

Multi-Omics Analysis Identifies Immune Regulatory Networks in Sepsis-Associated Liver Injury: Experimental Validation and Clinical Relevance

Key Points

Abstract

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