Molecular typing of sepsis-induced acute lung injury and its relationship with the immune microenvironment

Sepsis-associated Acute Lung Injury (SALI) represents a prevalent and life-threatening complication among patients with sepsis. Its pathogenesis involves lipid metabolism disorders and abnormal ferroptosis pathways. This research aims to identify unique biological markers for SALI and explore their diagnostic and immune regulatory roles using integrated bioinformatics analysis combined with experimental validation. We used the SALI cell model to study LPS-induced macrophage inflammation and related changes. Additionally, we analyzed gene expression using the GSE66890 and GSE32707 datasets. WGCNA identified gene modules in biological pathways, and five machine learning algorithms selected core diagnostic genes to build a model, which was then evaluated in the training set. Immune infiltration analysis assessed correlations with immune cells. Consensus clustering categorized patients into disease subtypes. GSVA compared signaling pathways and physiological responses. The SALI cell model revealed that LPS-induced macrophage inflammation leads to dyslipidemia and ferroptosis. Differential expression analysis identified 1585 differential genes, including 805 upregulated and 780 downregulated genes. WGCNA analysis revealed that genes within the MEpink module exhibited significant enrichment in apoptosis and lipid metabolism-related pathways. Five machine learning algorithms identified SLC7A11, ARNTL, and LCN2 as core diagnostic genes. The diagnostic model achieved an AUC of 0.82. Immune analysis indicated that ARNTL positively correlates with neutrophil infiltration (r = 0.50), while SLC7A11 negatively correlates with M0 macrophages (r = −0.40). Consensus clustering revealed two disease subtypes. GSVA showed significant differences in Notch/Wnt signaling and hypoxia responses between these subtypes (p < 0.01). This study establishes, for the first time, a SALI molecular typing system based on the lipid metabolism-ferroptosis axis. It provides novel biological markers for early clinical diagnosis and reveals how immune microenvironment heterogeneity regulates disease progression.