Identification of ferroptosis-related key genes associated with immune infiltration in sepsis by bioinformatics analysis and in vivo validation.

ABSTRACT

OBJECTIVES: Sepsis is a life-threatening infectious disease in which an immune inflammatory response is triggered. The potential effect of ferroptosis-related genes (FRGs) in inflammation of sepsis remained unclear. We focused on identifying and validating core FRGs and their association with immune infiltration in blood from currently all patients with sepsis. METHODS: All current raw data of septic blood were obtained from Gene Expression Omnibus. After removing the batch effect merging into a complete dataset and obtaining Diferentially expressed genes (DEGs). Common cross-talk genes were identified from DEGs and FRGs. WGCNA, GO, KEGG, PPI, GESA, ROC curves, and LASSO regression analysis were performed to indentify and validate key genes based on external septic datasets. Infiltrated immune cells in 2 hub genes (MAPK14 and ACSL4) were conducted using CIBERSORT algorithm and Spearman correlation analysis. Further, the expressions of 2 core FRGs were verified in the LPS-induced ALI and cardiac injury sepsis mice. RESULTS: MAPK14 and ACSL4 were identified, mostly enriched in T cell infiltration through NOD-like receptor signaling pathway according to the high or low 2 hub genes expression. The upregulated 2 ferroptosis-related genes were validated in LPS-induced ALI and cardiac injury mice, accompanied by upregulation of the NLRP3 pathway. CONCLUSION: MAPK14 and ACSL4 could become robustly reliable and promising biomarkers for sepsis by regulating ferroptosis through the NLRP3 pathway, which is mainly associated with T-cell infiltration.