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

Abstract

Zhile Li, Han Gan, Siyuan Li, Yuchen Xue, Kai Luo, Kai Huang, Yunqian Zhang, Yan Wang, Lai Jiang, Hui Zhang Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Lai Jiang; Hui Zhang, Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, People’s Republic of China, Email [email protected]; [email protected]: 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.Keywords: sepsis, SLI, ferroptosis, bioinformatics, HIF-1α, phloretin

Keywords

• sepsis
• sli
• ferroptosis
• bioinformatics
• hif-1α，phloretin