Abstract
Pneumonia-induced sepsis (PIS) is a life-threatening condition with high mortality rates, necessitating the identification of biomarkers and therapeutic targets. Sphingolipid, particularly ceramides, are pivotal in modulating immune responses and determining cell fate. In this study, we identified a novel gene signature related to sphingolipid metabolism, comprising ACER3, UGCG, and GBA, which are key enzymes involved in the synthesis and metabolism of ceramides. This signature, termed the "AUG model", demonstrated strong diagnostic performance and modest prognostic efficacy across both training (GSE65682) and validation (E-MTAB-1548 and E-MTAB-5273) datasets. A clinical cohort comprising 20 PIS patients, 31 pneumonia cases, and 11 healthy controls further validated the increased expression of AUG genes at both mRNA and protein levels in peripheral blood samples upon admission. Our comprehensive analysis of bulk and single-cell transcriptome datasets revealed that these genes are implicated in immune cell death pathways, including autophagy and apoptosis. Additionally, cell-communication analysis indicated that enhanced macrophage migration inhibitory factor (MIF) signaling may be associated with dysregulated sphingolipid metabolism, potentially driving the inflammatory cascade. This study identifies a novel predictive model for PIS, highlighting the role of sphingolipid metabolism-related genes in disease progression and suggesting potential therapeutic targets for sepsis management.