Abstract

Background Sepsis is a life-threatening condition associated with high mortality rates, claiming millions of lives globally each year. To improve prognostic prediction in sepsis, this study aimed to establish a lipid metabolism-associated gene signature for risk stratification and immune function evaluation.

Methods Using the sepsis dataset GSE65682 (Gene Expression Omnibus, GEO), lipid metabolism-associated genes were identified via GeneCards and intersection analysis. Hub genes selection integrated Univariate Cox, Least Absolute Shrinkage and Selection Operator (LASSO), and Multivariate Cox regression. Patients were stratified into high/low-risk groups by median risk scores. Prognostic performance was validated by Kaplan-Meier analysis and Receiver Operating Characteristic curves (ROC). Immune heterogeneity was analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), CIBERSORT, and correlation networks.

Results A 9-gene prognostic signature (Aryl Hydrocarbon Receptor Repressor, AHRR; Ceroid-Lipofuscinosis, Neuronal 8, CLN8; Fatty Acid Synthase, FASN; Lanosterol Synthase, LSS; Mediator Complex Subunit 29, MED29; Platelet-Activating Factor Acetylhydrolase IB Subunit Alpha, PAFAH1B1; Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Gamma, PIP5K1C; Tribbles Pseudokinase 3, TRIB3; UDP-Glucose Ceramide Glucosyltransferase, UGCG) demonstrated robust predictive value. High-risk patients showed poor survival (KM, p=6.75 × e⁻⁸;ROC AUC: 0.951) and enriched Chemokine Receptor (CCR) and parainflammation, while low-risk individuals exhibited elevated higher infiltration levels of Tumor-infiltrating lymphocytes(TIL), type_II_IFN_Response, Treg, and macrophages . Immune network analyses revealed coordinated interactions: activated NK cells synergized with M1 macrophages (r=0.44) but antagonized resting NK cells (r=-0.62). Immune checkpoints CD86/TNFSF4 were upregulated in low-risk patients, contrasting with CD200R1 suppression.

Conclusion This study successfully established a lipid metabolism-derived gene signature that provides a clinically actionable tool for prognostic stratification in sepsis patients, helping personalized clinical decision-making and facilitating early interventions.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

Not applicable.

Funding Statement

Yes

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AbbreviationsAHRRAryl Hydrocarbon Receptor Repressor;APACHE IIacute physiology and chronic health evaluation II;ATP2A2,ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2;AUCarea under the curve;BMXBMX Non-Receptor Tyrosine Kinase;CCRChemokine Receptor;CD200R1cluster of differentiation 200 receptor 1;CD244cluster of differentiation 244;CD8+ T cellcluster of differentiation 8-positive T lymphocyte;CD86cluster of differentiation 86;C-indexconcordance index;CIsconfidence intervals;CLN8Ceroid-Lipofuscinosis, Neuronal 8;COX19Cytochrome c oxidase assembly protein COX19 ;CRPC-reactive protein;CTLA-4cytotoxic T-lymphocyte-associated protein 4;CXCL10C-X-C motif chemokine ligand 10;CYP51A1Cytochrome P450 family 51 subfamily A member 1;DECR12,4-dienoyl-CoA reductase 1;DEGdifferentially expressed gene;EPHA2Epoxide Hydrolase 2;ERKextracellular signal- regulated kinase;EVextracellular vesicle;FAOfatty acid oxidation;FASNFatty Acid Synthase;FCER1AFc Fragment Of IgE Receptor Ia;GEOGene Expression Omnibus;GPCPD1Glycerophosphocholine phosphodiesterase 1;HAPhospital- acquired pneumonia;HDLhigh-density lipoprotein;HMGB1high mobility group box 1 protein;HRhazard ratios;IFNGR2interferon gamma receptor 2;I-FABPintestinal fatty acid binding protein;IL-10interleukin 10;LASSOLeast Absolute Shrinkage and Selection Operator;LDL-Clow-density lipoprotein cholesterol;LIPALipase A, lysosomal acid type;LMAGslipid metabolism-associated genes;LSSLanosterol Synthase;MAPK14Mitogen-Activated Protein Kinase 14;MCP-1monocyte chemotactic protein-1;MED29Mediator Complex Subunit 29;MODSmultiple organ dysfunction syndrome;MYD88myeloid differentiation primary response 88;NAnot available;NAAAN-acylethanolamine acid amidase;NF-κBnuclear factor kappa B;non-HAPnon-hospital-acquired pneumonia;PAFAH1B1Platelet Activating Factor Acetylhydrolase 1B Regulatory Subunit 1;PAFAH2Platelet Activating Factor Acetylhydrolase 2;PD-1programmed cell death protein 1;PD-L1programmed death- ligand 1;PCTprocalcitonin;PI4Pphosphatidylinositol 4-phosphate;PIP5K1CPhosphatidylinositol-4-Phosphate 5-Kinase Type 1 Gamma;PLIN2Perilipin 2 ;PTGDSProstaglandin D2 synthase;PTPaseProtein Tyrosine Phosphatase;RNA-seqRNA-sequencing;ROCreceiver operating characteristic curves;SOFAsequential organ failure assessment;ssGSEAsingle-sample Gene Set Enrichment Analysis;STAT1signal transducer and activator of transcription 1;STAT3signal transducer and activator of transcription 3;ST3GAL5ST3 beta-galactoside alpha-2,3- sialyltransferase 5;TILTumor-infiltrating lymphocytes;TLRToll-like receptor;TLR4Toll-like receptor 4;TNFRSF14tumor necrosis factor receptor superfamily member 14;TNFSF14tumor necrosis factor superfamily member 14;TNFSF4tumor necrosis factor superfamily member 4;TRIB3Tribbles Pseudokinase 3;UGCGUDP- Glucose Ceramide Glycosyltransferase.