Comprehensive analysis of the role of diverse programmed cell death patterns in sepsis.

Summary

Integrative bulk and single-cell transcriptomics reveal four upregulated programmed cell death pathways in sepsis and position monocytes as central hubs linking cell death, metabolism, and immune communication. An 18-gene Cell Death-associated Signature (CDS) achieved high diagnostic AUCs across public datasets and an independent RNA-seq cohort, supporting its utility for diagnosis and risk stratification.

Key Findings

• Four PCD pathways—ferroptosis, disulfidptosis, NETosis, and entotic cell death—were significantly upregulated and correlated with immune infiltration in sepsis.
• An 18-gene CDS risk score achieved AUCs of 0.961 and 0.844 in public datasets and 0.975 in an independent RNA-seq cohort.
• Single-cell analyses highlighted monocytes as dominant effectors with metabolic reprogramming and dysregulated intercellular signaling (MIF–CXCR4, ANXA1–FPR2, HLA–KIR).

Clinical Implications

While exploratory, the CDS score could evolve into a diagnostic/triage assay and guide precision immunomodulation targeting monocyte-driven PCD–metabolic axes. Prospective clinical validation is warranted before adoption.

Limitations

• Observational omics study without interventional validation
• Potential batch effects and limited clinical phenotyping across integrated datasets

Future Directions

Prospective, multicenter validation of the CDS score; development of clinical-grade assays; interventional studies targeting monocyte PCD–metabolic pathways; and evaluation of predictive value for immunotherapies.