Abstract
BackgroundIschemic stroke (IS) is a principal contributor to long-term disability in adults. A new cell death mediated by iron is ferroptosis, characterized by lethal aggregation of lipid peroxidation. However, a paucity of ferroptosis-related biomarkers early identify IS until now. This study investigated potential ferroptosis-related gene pair biomarkers in IS and explored their roles in immune infiltration.ResultsIn total, we identified 6 differentially expressed ferroptosis-related genes (DEFRGs) in the metadata cohort. Of these genes, 4 DEFRGs were incorporated into the competitive endogenous RNA (ceRNA) network, including 78 lncRNA-miRNA and 16 miRNA-mRNA interactions. Based on relative expression values of DEFRGs, we constructed gene pairs. An integrated scheme consisting of machine learning algorithms, ceRNA network, and gene pair was proposed to screen the key DEFRG biomarkers. The receiver operating characteristic (ROC) curve witnessed that the diagnostic performance of DEFRG pair CDKN1A/JUN was superior to that of single gene. Moreover, the CIBERSORT algorithm exhibited immune infiltration landscapes: plasma cells, resting NK cells, and resting mast cells infiltrated less in IS samples than controls. Spearman correlation analysis confirmed a significant correlation between plasma cells and CDKN1A/JUN (CDKN1A: r = − 0.503, P < 0.001, JUN: r = − 0.330, P = 0.025).ConclusionsOur findings suggested that CDKN1A/JUN could be a robust and promising gene-pair diagnostic biomarker for IS, regulating ferroptosis during IS progression via C9orf106/C9orf139-miR-22-3p-CDKN1A and GAS5-miR-139-5p/miR-429-JUN axes. Meanwhile, plasma cells might exert a vital interplay in IS immune microenvironment, providing an innovative insight for IS therapeutic target.
Highlights
Ischemic stroke (IS) is a principal contributor to long-term disability in adults
After interacting with ferroptosis-related genes, we focused on 6 consistent Differentially expressed ferroptosis-related gene (DEFRG) (CDKN1A, CXCL2, DDIT4, JUN, SLC7A5, and ZFP36) for further analysis, and all of them were up-regulated in IS
Immune infiltration landscapes To understand the roles of CDKN1A/JUN in the brain microenvironment during IS process, we investigated immune cells landscapes and their relationship with CDKN1A/JUN
Summary
A new cell death mediated by iron is ferroptosis, characterized by lethal aggregation of lipid peroxidation. This study investigated potential ferroptosis-related gene pair biomarkers in IS and explored their roles in immune infiltration. Ferroptosis is a newly recognized type of regulated cell death involved with the intracellular iron-mediated toxic accumulation of lipid peroxidation [5]. The possible molecular mechanisms of ferroptosis involve abnormal iron metabolism, lipid peroxidation, and some critical enzymes (like GPX4) [9]. Guozhong Chen et al [22] reported that MAP1LC3B, PTGS2, and TLR4 could be potential ferroptosis-related biomarkers for IS via bioinformatics, and further explored potential therapeutic compounds, such as Zinc11679756 (Eltrombopag). Exploring the reliable predictive gene pair biomarkers and specific regulatory details pertaining to ferroptosis in IS still be enormous challenges
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