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

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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.

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