Integrated Transcriptomic Analysis of S100A8/A9 as a Key Biomarker and Therapeutic Target in Sepsis Pathogenesis and...

Area of Science:

• Molecular biology
• Immunology
• Computational biology

Background:

• Sepsis is a life-threatening condition characterized by dysregulated immune responses and multi-organ failure.
• S100A8/A9 proteins act as damage-associated molecular patterns (DAMPs), exacerbating inflammation via Toll-like receptor 4 (TLR4) and RAGE pathways.
• Elevated S100A8/A9 levels are linked to sepsis severity, indicating potential as biomarkers and therapeutic targets.

Purpose of the Study:

• To investigate the role of S100A8/A9 in sepsis pathophysiology using integrated transcriptomic approaches.
• To identify potential therapeutic targets and drug repurposing strategies for sepsis treatment.

Main Methods:

• Integration of single-cell RNA sequencing (scRNA-seq) for cell-type-specific immune profiling and bulk RNA sequencing (RNA-seq) for global transcriptomic analysis.
• Identification of eight key protein targets (S100A8, S100A9, S100A6, NAMPT, FTH1, B2M, KLF6, SRGN) from transcriptomic data.
• Application of AI models (PLAPT) for predicting drug-target interactions and subsequent validation using molecular docking and dynamics simulations.

Main Results:

• The study elucidated the S100A8/A9-driven inflammatory cascade and its impact on immune cell interactions in sepsis.
• Integration of scRNA-seq and RNA-seq provided high-resolution insights into cellular heterogeneity and inflammatory pathways.
• AI-driven drug repurposing identified potential therapeutic candidates by predicting interactions between identified protein targets and approved drugs.

Conclusions:

• Combined transcriptomic analyses are powerful tools for understanding sepsis complexity and identifying therapeutic strategies.
• S100A8/A9 proteins are critical mediators in sepsis, serving as potential diagnostic and prognostic biomarkers.
• This study provides a foundation for developing precision medicine approaches in sepsis management through drug repurposing.