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 + T cells (Act. CD4T) as the cell subset contributing most significantly to sepsis pathogenesis. From 81 Act. CD4T marker genes, MR analysis identified four genes with a significant causal effect on sepsis risk: RPLP0 was identified as a causal risk factor (OR: 1. 272; 95% CI: 1. 031–1. 569), while CD52 (OR: 0. 903), RPS15A (OR: 0. 954), and RPS18 (OR: 0. 908) were identified as causal protective factors (all p0. 05). Clinical qPCR validation confirmed that RPLP0 was significantly upregulated in sepsis patients, while CD52, RPS15A, and RPS18 were downregulated. Functional analysis revealed these genes converge on a novel “Metabolism–Proteostasis–Immunity” regulatory axis, where RPLP0 drives a pathogenic program (HIF-1, IL-17, ERS) and RPS15A/RPS18 mediate a protective program (AMPK, mTORC1 inhibition). 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.
Zhou et al. (Thu,) studied this question.