Bioinformatics Identification and Validation of Ferroptosis-Related Key Genes and Therapeutic Compounds in Septic Lung Injury.

BACKGROUND: Septic lung injury (SLI) is a severe condition with high mortality, and ferroptosis, a form of programmed cell death, is implicated in its pathogenesis. However, the explicit mechanisms underlying this condition remain unclear. This study aimed to elucidate and validate key ferroptosis-related genes involved in the pathogenesis of SLI through bioinformatics analysis and experimental validation. METHODS: Microarray data related to SLI from the GSE130936 dataset were downloaded from the Gene Expression Omnibus (GEO) database. These data were then intersected with the FerrDb database to obtain ferroptosis-related differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks and functional enrichment analysis were employed to identify key ferroptosis-related DEGs. The Connectivity Map (c-MAP) tool was used to search for potential compounds or drugs that may inhibit ferroptosis-related DEGs. The transcriptional levels of the key genes and potential therapeutic compounds were verified in an LPS-induced mouse model of lung injury. The expression of these key genes was further verified using the GSE60088 and GSE137342 datasets. RESULTS: 38 ferroptosis-related DEGs were identified between the septic and control mice. PPI network analysis revealed four modules, the most significant of which included eight ferroptosis-related DEGs. Functional enrichment analysis showed that these genes were enriched in the HIF-1 signaling pathway, including IL-6 (Interleukin-6), TIMP1 (Tissue Inhibitor of Metalloproteinase 1), HIF-1α (Hypoxia-Inducible Factor-1α), and HMOX1 (Heme Oxygenase-1). Phloretin, a natural compound, was identified as a potential inhibitor of these genes. Treatment with phloretin significantly reduced the expression of these genes (p < 0.05), mitigated lung injury, improved inflammatory profiles by approximately 50%, and ferroptosis profiles by nearly 30% in the SLI models. CONCLUSION: This study elucidates the significant role of ferroptosis in SLI and identifies phloretin as a potential therapeutic agent. However, further research, particularly involving human clinical trials, is necessary to validate these findings for clinical use.