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. 2022 Sep 29:13:1015491.
doi: 10.3389/fimmu.2022.1015491. eCollection 2022.

Identification of cross-talk pathways and ferroptosis-related genes in periodontitis and type 2 diabetes mellitus by bioinformatics analysis and experimental validation

Shengyuan Pan  1   2   3 , Bo Hu  1   2   3 , Jicheng Sun  1   2   3 , Zun Yang  1   2   3 , Wenliang Yu  1   2   3 , Zangmin He  1   2   3 , Xiang Gao  1   2   3 , Jinlin Song  1   2   3
Affiliations

Identification of cross-talk pathways and ferroptosis-related genes in periodontitis and type 2 diabetes mellitus by bioinformatics analysis and experimental validation

Shengyuan Pan et al. Front Immunol. .

Abstract

Purpose: There is a bidirectional relationship between periodontitis and type 2 diabetes mellitus (T2DM). The aim of this study was to further explore the pathogenesis of this comorbidity, screen out ferroptosis-related genes involved in the pathological process, and predict potential drug targets to develop new therapeutic strategies.

Methods: Common cross-talk genes were identified from periodontitis datasets (GSE16134, GSE10334 and GSE106090) and T2DM databases (DisGeNET and GeneCard). Then, GO and KEGG enrichment analyses, PPI network analysis and hub gene identification were performed. The association between ferroptosis and periodontitis with T2DM was investigated by Pearson correlation analysis. Core ferroptosis-related cross-talk genes were identified and verified by qRT-PCR. Potential drugs targeting these core genes were predicted via DGIDB.

Results: In total, 67 cross-talk genes and two main signalling pathways (immuno-inflammatory pathway and AGE-RAGE signalling pathway) were identified. Pearson correlation analysis indicated that ferroptosis served as a crucial target in the pathological mechanism and treatment of periodontitis with T2DM. IL-1β, IL-6, NFE2L2 and ALOX5 were identified as core ferroptosis-related genes and the qRT-PCR detection results were statistically different. In total, 13 potential drugs were screened out, among which, Echinacea and Ibudilast should be developed first.

Conclusions: This study contributes to a deeper understanding of the common pathogenesis of periodontitis and T2DM and provides new insights into the role of ferroptosis in this comorbidity. In addition, two drugs with potential clinical application value were identified. The potential utility of these drugs requires further experimental investigation.

Keywords: drug prediction; ferroptosis; pathway; periodontitis; type 2 diabetes mellitus.

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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
Study design flowchart, volcano diagram and venn diagram. (A) The detailed flowchart of the study. (B) The volcano map of GSE16134. (C) The volcano map of GSE10334. (D) The volcano map of GSE106090. Upregulated genes are marked in red; downregulated genes are marked in blue. (E) Venn diagram of cross-talk genes from three datasets and two databases.
Figure 2
Figure 2
Functional and pathway enrichment analysis of cross-talk genes. (A) Top 10 BP terms. (B) Top 10 CC terms. (C) Top 10 MF terms. (D) Top 15 KEGG terms. P < 0.05 was considered significant.
Figure 3
Figure 3
The results of PPI network, hub genes and significant modules. (A) PPI network of cross-talk genes. (B) Top 10 hub genes. (C) Significant module 1 (contained 19 nodes and 151 edges). (D) Significant module 2 (contained 4 nodes and 5 edges).
Figure 4
Figure 4
Correlation analysis between cross-talk genes and ferroptosis-related genes. Genes in the vertical line are cross-talk genes and genes in in the horizontal line are FRGs. Red indicates a positive correlation, blue indicates a negative correlation. The size of circle designates the correlation coefficient between cross-talk genes and ferroptosis-related genes.
Figure 5
Figure 5
Venn diagram and enrichment analysis of FR-cross-talk genes. (A) Seven FR-cross-talk genes were identified by venn diagram. (B)The GO and KEGG enrichment analysis of FR-cross-talk genes.
Figure 6
Figure 6
ROC analysis. (A–G) ROC analysis results of IL-1β, IL-6, ALOX5, NFE2L2, GDF15, SCD and TFAP2A, respectively.
Figure 7
Figure 7
The results of qRT-PCR. (A–D) The relative expression levels of IL-1β, IL-6, ALOX5 and NFE2L2 between different groups using qRT-PCR. (E) Differentially expressed factors were shown as a Radar Chart. The qRT-PCR data were analysed by ANOVA. A p-value < 0.05 was considered statistically significant. All data were presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
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