Integrative Analysis Identifies Lactylation-Associated Hub Genes in Septic Cardiomyopathy

Area of Science:

• Genomics and Bioinformatics
• Cardiovascular Research
• Immunology

Background:

• Septic cardiomyopathy (SCM) is a severe complication of sepsis with high mortality.
• The molecular mechanisms underlying SCM remain poorly understood, hindering effective treatment.

Purpose of the Study:

• To identify key molecular players and pathways involved in septic cardiomyopathy.
• To explore potential diagnostic biomarkers for SCM.
• To validate bioinformatic findings in an experimental model.

Main Methods:

• Integrated bioinformatics analysis of human transcriptomic data (GEO: GSE79962).
• Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms (Boruta, RF, SVM-RFE) for hub gene identification.
• Gene Set Enrichment Analysis (GSEA), immune infiltration profiling (CIBERSORT), and Protein-Protein Interaction (PPI) network construction.
• Experimental validation in a lipopolysaccharide (LPS)-induced septic mouse model.

Main Results:

• Identified three hub genes (GADD45B, STAT3, SLC7A5) significantly dysregulated in SCM with high diagnostic potential (AUC > 0.95).
• Observed activation of innate immune/inflammatory pathways and suppression of cardiac energy metabolism pathways.
• Linked hub genes to the cS-STING signaling pathway and correlated their expression with specific immune cell infiltrations.
• Confirmed hub gene dysregulation in LPS-induced septic mouse hearts.

Conclusions:

• GADD45B, STAT3, and SLC7A5 are identified as central hub genes in septic cardiomyopathy.
• These genes are implicated in immune dysregulation and metabolic disturbances within the septic heart.
• Lactylation is proposed as a novel regulatory mechanism for these hub genes in SCM, warranting further investigation.