Dataset Information

Establishment of Ferroptosis-Related Key Gene Signature and Its Validation in Compression-Induced Intervertebral Disc Degeneration Rats.

ABSTRACT: Cell death and functional loss of nucleus pulposus cell play essential roles in intervertebral disc degeneration (IDD). Ferroptosis is a newly identified cell death type, and its role in IDD is still under investigation. Identifying the key genes of ferroptosis in IDD helps to identify the therapeutic targets of IDD. In this study, we downloaded the human IDD mRNA microarray data from the Gene Expression Omnibus and ferroptosis genes from FerrDb, then performed a series of analyses using strict bioinformatics algorithms. In general, we obtained 40 ferroptosis-related differential expression genes (FerrDEGs) and identified six ferroptosis key gene signatures, namely, ATF3, EIF2S1, AR, NQO1, TXNIP, and AKR1C3. In addition, enrichment analysis of the FerrDEGs was conducted, the protein-protein interaction network was constructed, the correlations between ferroptosis key genes and immune infiltrating cells were analyzed, and the lncRNA-miRNA-mRNA ceRNA network was constructed. In particular, ATF3 and EIF2S1 showed the strongest correlation with immune cell function, which might lead to the development of IDD. Finally, the expressions of ferroptosis key genes were verified in the rat compression-induced IDD. In conclusion, this preliminary study analyzed and verified the mechanism of ferroptosis in IDD, laid a foundation for the follow-up study of the mechanism of ferroptosis in IDD, and provided new targets for preventing and delaying IDD.

SUBMITTER: Guo J

PROVIDER: S-EPMC9937767 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Establishment of Ferroptosis-Related Key Gene Signature and Its Validation in Compression-Induced Intervertebral Disc Degeneration Rats.

Guo Jiangbo J Yang Yilin Y Niu Junjie J Luo Zongping Z Shi Qin Q Yang Huilin H

Oxidative medicine and cellular longevity 20230210

Cell death and functional loss of nucleus pulposus cell play essential roles in intervertebral disc degeneration (IDD). Ferroptosis is a newly identified cell death type, and its role in IDD is still under investigation. Identifying the key genes of ferroptosis in IDD helps to identify the therapeutic targets of IDD. In this study, we downloaded the human IDD mRNA microarray data from the Gene Expression Omnibus and ferroptosis genes from FerrDb, then performed a series of analyses using strict ...[more]

PMID: 36819777

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Project description:Background and objectiveIntervertebral disc degeneration (IDD) is a complex multifactorial and irreversible pathological process. In IDD, multiple competing endogenous RNAs (ceRNA, including mRNA, lncRNA, and pseudogenes) can compete to bind with miRNAs. However, the potential metabolic signatures in nucleus pulposus (NP) cells remain poorly understood. This study investigated key metabolic genes and the ceRNA regulatory mechanisms in the pathogenesis of IDD based on microarray datasets.MethodsWe retrieved and downloaded four independent IDD microarray datasets from the Gene Expression Omnibus. Combining the predicted interactions from online databases (miRcode, miRDB, miRTarBase, and TargetScan), differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) were identified. A ceRNA network was constructed and annotated using GO and KEGG pathway enrichment analyses. Moreover, we searched the online metabolic gene set and used support vector machine (SVM) to find the critical metabolic DEmRNA(s) and other DERNAs. Differential gene expression was validated with a merged dataset.ResultsA total of 45 DEmRNAs, 36 DElncRNAs, and only one DEmiRNA (miR-338-3p) were identified in the IDD microarray datasets. GO and KEGG pathway enrichment analyses revealed that the DEmRNAs were predominantly enriched in the PI3K-Akt signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, apoptosis, and cellular response to oxidative stress. Based on SVM screening, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK/FBPase) 2 is the critical metabolic gene with lower expression in IDD, and AC063977.6 is the key lncRNA with lower expression in IDD. The ceRNA hypothesis suggests that AC063977.6, miR-338-3p (high expression), and PFKFB2 are dysregulated as an axis in IDD.ConclusionsThe results suggest that lncRNA AC063977.6 correlate with PFKFB2, the vital metabolic signature gene, via targeting miR-338-3p during IDD pathogenesis. The current study may shed light on unraveling the pathogenesis of IDD.

Project description:Ferroptosis and immune infiltration play an important role in the pathogenesis of intervertebral disc degeneration (IDD). However, there is still a lack of comprehensive analysis on the interaction between ferroptosis-related genes (FRGs) and immune microenvironment in IDD patients. Therefore, this study aims to explore the correlation between FRGs characteristics and immune infiltration in the progression of IDD. The expression profiles (GSE56081 and GSE70362) and FRGs were downloaded from the comprehensive gene expression omnibus (GEO) and FerrDb database, respectively, and the differences were analyzed using R. The intersection of IDD related differential genes (DEGs) and FRGs was taken as differentially expressed FRGs (DE-FRGs) and GO and KEGG enrichment analysis was conducted. Then, we used least absolute shrinkage and selection operator (LASSO) regression algorithm and support vector machine (SVM) algorithm to screen feature genes and draw ROC curve judge the diagnostic value of key DE-FRGs. Then CIBERSORT algorithm is used to evaluate the infiltration of immune cells and analyze the correlation between key DE-FRGs and immune infiltration. Based on the analysis results, we conducted single gene GSEA analysis on key DE-FRGs. RT-PCR and immunohistochemistry further verified the clinical value of the results of biochemical analysis and screening. Seven key DE-FRGs were screened, including the upregulated genes NOX4 and PIR, and the downregulated genes TIMM9, ATF3, ENPP2, FADS2 and TFAP2A. Single gene GSEA analysis further elucidates the role of DE-FRGs in IDD associated with ferroptosis. Correlation analysis showed that seven key DE-FRGs were closely related to immune infiltration in the development of IDD. Finally, RT-PCR and immunohistochemical staining showed that NOX4, ENPP2, FADS2 and TFAP2A were statistically significant differences. In this study, we explored the connection between ferroptosis related characteristics and immune infiltration in IDD, and confirmed that NOX4, ENPP2, FADS2, and TFAP2A may become biomarkers and potential therapeutic targets for IDD.

Dataset Information

Establishment of Ferroptosis-Related Key Gene Signature and Its Validation in Compression-Induced Intervertebral Disc Degeneration Rats.

Publications

Establishment of Ferroptosis-Related Key Gene Signature and Its Validation in Compression-Induced Intervertebral Disc Degeneration Rats.

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