Unravelling Ferroptosis in Sepsis: A Comprehensive Integrative Transcriptomic Analysis Across Age and Disease Severity.

Abstract

Ferroptosis, an iron-dependent, regulated form of cell death, has been increasingly recognised as a pivotal driver of organ dysfunction and mortality in sepsis. Despite its importance, the transcriptomic regulation of ferroptosis in human sepsis has not been systematically characterised. Here, we present a comprehensive integrative analysis, combining 17 transcriptomic data sets from previously published studies involving blood samples from septic patients and healthy controls, encompassing microarray, bulk RNA sequencing, and single-cell RNA sequencing platforms. Our findings reveal that ferroptosis-related gene regulation intensifies with disease progression and is markedly more pronounced in adults. Single-cell analysis identified monocytes as the primary regulators of ferroptosis in peripheral blood during sepsis. Eleven core ferroptosis-related genes (ACSL1, ALOX5, CAPG, CREB5, MAPK14, MGST1, MICU1, QSOX1, SAT1, SIAH2, and SLC2A3) were consistently upregulated, serving as robust candidates for sepsis biomarkers, while additional genes correlated with disease severity, suggesting prognostic value. This large-scale integrative approach provides novel molecular insights into sepsis pathophysiology and identifies promising targets for improved diagnosis and therapy.