Metabolic gene-based clustering identifies the role of acyl-CoA synthetase long-chain family member 1 in sepsis.

Abstract

Sepsis patients display substantial metabolic heterogeneity. Here, we classify sepsis patients into distinct metabolic clusters using transcriptomic profiles of metabolism-related genes, aiming to uncover key metabolic drivers of disease progression. Unsupervised clustering identifies three metabolic gene signature clusters (MGSC1, MGSC2, and MGSC3), with MGSC2 exhibiting the greatest disease severity and an activated fatty acid metabolism profile. Pathway enrichment analysis highlights MGSC2-specific metabolic dysregulation, and LightGBM-based feature selection identifies acyl-CoA synthetase long-chain family member 1 (ACSL1) as the hallmark gene of MGSC2, which is significantly upregulated in septic peripheral blood mononuclear cells (PBMCs). Molecular docking and in vitro assays demonstrate that osthole, a natural coumarin derivative, directly targets ACSL1, reducing lipid peroxidation and ferroptosis in septic PBMCs. Single-cell RNA sequencing reveals that ACSL1 is predominantly overexpressed in a pathogenic monocyte subset, driving sepsis progression. These findings suggest that metabolic stratification can distinguish clinically relevant subtypes of sepsis, with ACSL1 representing a key therapeutic target. Furthermore, osthole shows potential as a targeted intervention by inhibiting ACSL1-mediated ferroptosis in PBMCs from sepsis patients.