Ferroptosis, Pyroptosis and Necroptosis-related Genes in Sepsis-induced Acute Respiratory Distress Syndrome and Immune Infiltration

Abstract

Abstract Purpose: Ferroptosis, pyroptosis, and necroptosis are interrelated and play an important role in the pathophysiology of sepsis-induced acute respiratory distress syndrome (ARDS). However, expression profiles of relates have rarely been used to explore the relationship between ferroptosis, pyroptosis, and necroptosis and sepsis-induced ARDS. Consequently, we aim to employ bioinformatics analysis to identify and confirm potential genes associated with ferroptosis, pyroptosis, and necroptosis in sepsis-induced ARDS. Methods: Gene expression matrices were obtained from the Gene Expression Omnibus (GEO) database and subjected to screening for differentially expressed ferroptosis, pyroptosis, and necroptosis-related genes (DEfpnRGs) in sepsis-induced acute respiratory distress syndrome (ARDS) using R software. Functional enrichment analyses were then conducted to investigate the potential biological functions of DEfpnRGs, followed by the construction of protein-protein interaction (PPI) networks. Subsequently, correlation analysis and receiver operating characteristic (ROC) curve analysis were employed to assess the DEfpnRGs. Furthermore, we investigated the correlation between these distinct genes and immune cells by employing the CIBERSORT algorithm and conducting spearman correlation analysis. Ultimately, the RNA expression of nine DEfpnRGs was confirmed through mRNA sequencing and qRT-PCR in blood samples obtained from individuals with sepsis-induced ARDS as well as from healthy controls. Results: We have identified a total of 32 DEfpnRGs, consisting of 19 up-regulated genes and 13 down-regulated genes. Notably, the correlation coefficients between CFLAR, FPR1, S100A12, and SIRPA with T cells follicular helper, FSCN1 with Monocytes, and GBP2, FPR1, and CFLAR with Mast cells resting were found to be less than -0.6, indicating a strong negative correlation. Conversely, the correlation coefficient between GBP2 and Neutrophils was greater than 0.6, suggesting a strong positive correlation. Nine genes (ELANE, CAMP, HMGCS1, TNIP1, SSBP1MYC, ADORA2A, LCN2, LTF, and MYC) with AUC>0.75 were considered possible to be sepsis-induced ARDS hub genes for ROC curve analysis.The results of mRNA sequencing and qRT-PCR confirmed that five of these hub genes were significantly upregulated in sepsis-induced ARDS, while three genes exhibited low expression levels in this condition. Conclusion: We identified an association between DEfpnRGs and immune infiltration in sepsis-induced ARDS and validated the promising diagnostic poteintial of ELANE, HMGCS1, TNIP1, SSBP1MYC, ADORA2A, LCN2, LTF, and MYC.