Prognostic stratification of sepsis through DNA damage response based RiskScore system: insights from single-cell...

Area of Science:

• Genomics
• Immunology
• Computational Biology

Background:

• Sepsis poses a significant threat, necessitating improved prognostic tools.
• DNA damage response (DDR) is implicated in sepsis pathogenesis.
• Current prognostic models for sepsis require enhancement.

Purpose of the Study:

• To develop a novel risk scoring system for sepsis prognosis based on DDR markers.
• To identify key DDR-associated genes for risk stratification.
• To explore the biological and immune characteristics of sepsis patients across different risk groups.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and WGCNA to identify DDR-associated genes.
• Cox proportional hazards LASSO regression to build a four-gene risk model (ARL4C, CD247, RPL7, RPL31).
• Validation using nomograms, calibration plots, DCA, and in vivo/in vitro assays (RT-PCR, ELISA, flow cytometry).

Main Results:

• scRNA-seq and bulk transcriptomics confirmed DDR levels correlate with sepsis prognosis.
• Elevated DDR activity was observed in monocytes, megakaryocytes, CD4+ T cells, and neutrophils.
• The four-gene risk score accurately stratified patients and predicted survival, with lower-risk groups showing enhanced immune cell infiltration and function.
• Experimental validation supported the role of the four genes, particularly ARL4C, in sepsis prognosis.

Conclusions:

• The DDR expression landscape provides insights into sepsis pathogenesis.
• A robust four-gene risk score model can aid in personalized sepsis treatment strategies.
• This risk score has potential clinical benefits for sepsis patient management.