Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb 6:14:1089796.
doi: 10.3389/fendo.2023.1089796. eCollection 2023.

Identification and validation of ferroptosis-related gene signature in intervertebral disc degeneration

Qian Xiang  1   2   3 , Yongzhao Zhao  1   2   3 , Weishi Li  1   2   3
Affiliations

Identification and validation of ferroptosis-related gene signature in intervertebral disc degeneration

Qian Xiang et al. Front Endocrinol (Lausanne). .

Abstract

Lower back pain (LBP) is a leading cause of disability in the elderly and intervertebral disc degeneration (IDD) is the major contributor to LBP. Ferroptosis is a newly discovered programmed cell death, characterized by iron-dependent lethal lipid peroxidation. Growing evidence has shown that ferroptosis plays important roles in various human diseases. However, the underlying mechanism of ferroptosis in IDD remains elusive. This study is aimed to uncover the key roles of ferroptosis in the pathogenesis and progression of IDD comprehensively. To investigate the ferroptosis related differentially expressed genes (FRDEGs) in IDD, we analyzed the microarray data from the Gene Expression Omnibus (GEO) database. Then we performed functional enrichment analysis and protein-protein interaction (PPI) network analysis, and screened out the hub FRDEGs. To further evaluate the predictive value of these hub FRDEGs, we performed ROC analysis based on the GSE124272 dataset. A total of 80 FRDEGs were identified, including 20 downregulated and 60 upregulated FRDEGs. The FRDEGs were primarily involved in the biological processes of response to chemical, and response to stress. KEGG pathway enrichment analysis showed that the FRDEGs were mainly involved in ferroptosis, TNF signaling pathway, HIF-1 signaling pathway, NOD-like receptor signaling pathway, and IL-17 signaling pathway. Ten hub OSRDEGs were obtained according to the PPI analysis, including HMOX1, KEAP1, MAPK1, HSPA5, TXNRD1, IL6, PPARA, JUN, HIF1A, DUSP1. The ROC analysis and RT-qPCR validation results suggested that most of the hub FRDEGs might be potential signature genes for IDD. This study reveals that ferroptosis might provide promising strategy for the diagnosis and treatment of IDD.

Keywords: ferroptosis; intervertebral disc degeneration; lower back pain; nucleus pulposus; oxidative stress.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Identification of the differentially expressed genes between IDD and control groups. (A) The volcano plot of the differentially expressed genes in GSE56081 microarray data from the GEO database, in which the X-axis refers to the -log10(p value) and the Y-axis refers to the log2(fold change). The red dots represent the upregulated genes, and the blue dots represent the downregulated genes; the gray dots represent the genes without significant differential expression. (B) Venn diagram of the differentially expressed genes analyzed according to GSE56081 and the ferroptosis-related genes based on FerrDb database.
Figure 2
Figure 2
The hierarchical cluster heatmap of the 80 ferroptosis related differentially expressed genes (FRDEGs). The color scale indicates the relative gene expression of each sample. The red represents upregulated genes in IDD group compared to control, and the blue represents downregulated genes in IDD group. Among these FRDEGs, 20 FRDEGs are downregulated and 60 FRDEGs are upregulated.
Figure 3
Figure 3
Functional enrichment analysis of the FRDEGs. (A) The top 10 significantly enriched GO terms in the category of biological process (BP) for the FRDEGs. (B) The top 10 significantly enriched GO terms in the category of cellular component (CC). (C) The top 10 significantly enriched GO terms in the category of molecular function (MF). (D) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the FRDEGs.
Figure 4
Figure 4
PPI analysis of the FRDEGs. (A) PPI analysis of these FRDEGs. (B) The top 10 hub FRDEGs. (C) Correlation analysis among the top 10 hub FRDEGs by Pearson analysis. (D) Correlation analysis between HSPA5 and JUN by Pearson analysis. (E) Correlation analysis between KEAP1 and MAPK1 by Pearson analysis.
Figure 5
Figure 5
Function analysis of the hub FRDEGs. (A) The top 10 significantly enriched GO terms in the category of biological process for these hub FRDEGs. (B) The top 10 significantly enriched GO terms in the category of cellular component. (C) The top 10 significantly enriched GO terms in the category of molecular function. (D) KEGG pathway analysis for these hub FRDEGs.
Figure 6
Figure 6
Validation of these hub FRDEGs based on the GSE124272 dataset. (A–J) ROC analysis of the ten hub FRDEGs, including HMOX1, KEAP1, MAPK1, HSPA5, TXNRD1, IL6, PPARA, JUN, HIF1A, and DUSP1. The X-axis represents the (1-Specificity), and the Y-axis represents the Sensitivity.
Figure 7
Figure 7
Validation of these hub FRDEGs in IDD cell model. (A) The cell viability of the rat NP cells treated with different concentrations of TBHP for 24 h was determined by the CCK-8 analysis. (B–K) The mRNA expression levels of these ten hub FRDEGs in the rat NP cells with or without TBHP treatment were determined by RT-qPCR assay. ns, not significant. ∗p < 0.05, ∗∗∗p < 0.001, n = 3.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Maher C, Underwood M, Buchbinder R. Non-specific low back pain. Lancet (2017) 389(10070):736–47. doi: 10.1016/s0140-6736(16)30970-9 - DOI - PubMed
    1. Zhou Z, Hui ES, Kranz GS, Chang JR, de Luca K, Pinto SM, et al. . Potential mechanisms underlying the accelerated cognitive decline in people with chronic low back pain: A scoping review. Ageing Res Rev (2022), 82:101767. doi: 10.1016/j.arr.2022.101767 - DOI - PubMed
    1. Binch ALA, Fitzgerald JC, Growney EA, Barry F. Cell-based strategies for ivd repair: Clinical progress and translational obstacles. Nat Rev Rheumatol (2021) 17(3):158–75. doi: 10.1038/s41584-020-00568-w - DOI - PubMed
    1. Xiang Q, Zhao Y, Lin J, Jiang S, Li W. The Nrf2 antioxidant defense system in intervertebral disc degeneration: Molecular insights. Exp Mol Med (2022) 54(8):1067–75. doi: 10.1038/s12276-022-00829-6 - DOI - PMC - PubMed
    1. Sakai D, Grad S. Advancing the cellular and molecular therapy for intervertebral disc disease. Adv Drug Delivery Rev (2015) 84:159–71. doi: 10.1016/j.addr.2014.06.009 - DOI - PubMed

Publication types