Multi-omics analysis and experimental validation identify ARG2 as a potential metabolic regulator linking metabolic dysregulation to inflammatory cell death in sepsis-induced acute lung injury

Introduction Sepsis-induced acute lung injury (SI-ALI) is a life-threatening complication of sepsis that is often difficult to diagnose early due to the lack of effective diagnostic methods. Although a strong link has been established between metabolic reprogramming and immune dysfunction, the role of metabolic changes in inflammatory cell death and pulmonary immune dysregulation in SI-ALI remains unclear. Methods We analyzed transcriptomic datasets from multiple cohorts in the GEO database and applied Gene Set Enrichment Analysis (GSEA) to identify pathway alterations. Three machine learning algorithms were utilized to screen for metabolism-related genes (MRGs) with diagnostic potential. To further investigate the core diagnostic gene, we performed virtual knockout analyses, molecular docking, and molecular dynamics simulations. Finally, in vitro and in vivo experiments, coupled with lipidomic analysis, were conducted to validate gene expression patterns, functional mechanisms, and the efficacy of targeted drug interventions. Results GSEA revealed prominent changes in metabolic pathways and cell death-related processes in SI-ALI. A four-gene signature comprising ARG2, FTH1, TSC1, and GNMT was established, which demonstrated good diagnostic performance and was validated in clinical samples. ARG2 was identified as the core gene of the diagnostic signature, and its expression was positively correlated with pro-inflammatory immune cell populations in SI-ALI. Virtual knockout analyses of ARG2 revealed alterations in inflammatory pathways, particularly those related to neutrophil chemotaxis and neutrophil extracellular trap (NET) formation. Tacedinaline was identified as a potential ARG2-targeting compound, with interactions supported by molecular docking and dynamics simulations. Experiments demonstrated that ARG2 inhibition and Tacedinaline treatment attenuated inflammatory responses and pulmonary endothelial barrier dysfunction in vitro , while reducing lung injury and neutrophil infiltration in vivo . Additionally, lipidomic analysis showed that ARG2 knockdown reduced inflammatory responses and intracellular ceramide accumulation, suggesting an association between ARG2 and sphingolipid remodeling. Discussion Overall, we identified a novel four-gene metabolic signature with diagnostic potential for SI-ALI. Our findings indicate that ARG2 is closely associated with cell death-related processes and immune dysregulation. These results not only provide new insights into the metabolic and immune mechanisms underlying SI-ALI but also highlight ARG2 and its targeted compound, Tacedinaline, as promising avenues for therapeutic intervention.