A synergistic multi-omics approach: causal sepsis drivers identified in activated CD4

Background: Sepsis is a life-threatening, heterogeneous syndrome with high mortality. This heterogeneity undermines current "one-size-fits-all" therapies and conventional biomarkers (e.g., PCT) lack prognostic power. A critical need exists to identify patient-specific endotypes and causal-driven therapeutic targets. Methods: We employed a synergistic multi-omics strategy to identify causal drivers of sepsis. First, we used single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (GSE175453) to identify the most pathologically relevant immune cell subpopulation. Next, we used marker genes from this subset as exposures in a two-sample Mendelian randomization (MR) study, using summary statistics from a large-scale sepsis GWAS (11,643 cases/474,841 controls; ieu-b-4980) and eQTL data (eQTLGen) to validate causal relationships. Findings were explored via in-silico functional-genomics (GSEA, GSVA) and validated via qPCR in a clinical cohort (5 sepsis vs. 5 healthy controls). Results: scRNA-seq analysis identified activated CD4 Conclusion: This study is to integrate scRNA-seq and MR to discover cell-specific causal genes for sepsis. The identified four-gene signature provides potentially robust, causally-validated biomarkers for patient stratification and reveals the "Metabolism-Proteostasis-Immunity" axis as a critical, therapeutically-targetable node in sepsis pathogenesis.