Single-Cell RNA Sequencing Combined with MEBOCOST Reveals Alveolar Macrophage-Mediated Immunometabolic Communication...

Background: Sepsis-induced acute lung injury (SI-ALI) leads to high mortality in critically ill patients, and no specific targeted treatments are available. Current studies mainly characterize intercellular crosstalk via protein-ligand-receptor frameworks, while metabolite-derived immune signal transmission is largely unclarified. Alveolar macrophages are located at the alveolar barrier and may act as central metabolic coordinators to trigger neutrophil-mediated lung inflammation, yet the complete metabolite signaling network has not been systematically mapped. Methods: We integrated single-cell and bulk transcriptomic datasets from CLP-induced septic mouse lungs. CellChat and MEBOCOST were jointly used to reconstruct protein-metabolite dual communication networks. LASSO regression and random forest were combined to screen core metabolic hub genes, followed by single-cell expression mapping and in vivo histology & qPCR validation. Results: We identified a pivotal alveolar macrophage-neutrophil immunometabolic axis dominated by iron-Slc40a1 and LTB4-Ltb4r1 signaling. Three hub genes (Pmvk, Slc2a1, Slc7a11) coordinately regulate inflammatory pathways, among which myeloid-enriched Slc7a11 balances cellular redox and paracrine inflammatory responses. Conclusions: This study establishes the first dual-layer cell communication atlas for SI-ALI, proposes a macrophage-centered metabolic inflammatory regulatory model, and highlights Slc7a11 as a potential therapeutic target for septic lung injury.