Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Intracerebral Hemorrhage.

Xinhe Li,Tongye Liu,Yuyang Wang,Qiang Wang,Guanghui Zeng,Yiteng Cui,Pingping Meng

doi:10.3389/fnins.2021.661663

Xinhe Li, Tongye Liu + Show 5 more

Open Access

https://doi.org/10.3389/fnins.2021.661663

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Abstract

Intracerebral hemorrhage (ICH) is a dangerous neurological disease. The mechanism of ferroptosis in ICH remains unclear. Using bioinformatics analysis, we aimed to identify the key molecules involved in ferroptosis and provide treatment targets for ICH to further explore the mechanism of ferroptosis in ICH. GSE24265 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes. A total of 45 differentially expressed genes (DEGs) were selected, most of which were involved in the TNF signaling pathway and oxidative stress response. Key modules constructed by the protein–protein interaction (PPI) network analysis and screening of genes related to the TNF signaling pathway led to the confirmation of the following genes of interest: MAPK1, MAPK8, TNFAIP3, ATF4, and SLC2A1. Moreover, MAPK1 was one of the key genes related to TNF signaling and oxidative stress, and it may play an important role in ferroptosis after cerebral hemorrhage. The MAPK1-related molecules included hsa-miR-15b-5P, hsa-miR-93-5P, miR-20b-5p, SNHG16, XIST, AC084219.4, RP11-379K17.11, CTC-444N24.11, GS1-358P8.4, CTB-89H12.4, RP4-773N10.5, and FGD5-AS1. We also generated a hemorrhage rat model, which was used to conduct exercise intervention in ICH rats, and qRT-PCR was used to assess the expression levels of our genes of interest. The mRNA levels after cerebral hemorrhage showed that MAPK1, ATF4, SLC2A1, and TNFAIP3 were upregulated, whereas MAPK8 was downregulated. Treadmill training increased the expression of anti-inflammatory molecules TNFAIP3 and SLC2A1 and reduced the expression of MAPK1, ATF4, and MAPK8, indicating that treadmill training may be utilized as antioxidant therapy to decrease neuronal ferroptosis. The results of this study indicated that the MAPK1-related mRNA–miRNA–lncRNA interaction chain could be potentially employed as a biomarker of the inception and progression of ferroptosis after cerebral hemorrhage.

Highlights

MATERIALS AND METHODSIntracerebral hemorrhage (ICH) is a disease associated with high mortality, disability, and dysfunction (Qureshi et al, 2001)
The results indicated that the expression levels of MAPK1, ATF4, SLC2A1, and TNFAIP3 were visibly higher and that the expression of MAPK8 was lower in ICH rats than in the sham controls
The present study identified the key genes involved in ferroptosis and further explored the mechanisms of ferroptosis in ICH

Summary

MATERIALS AND METHODS

Intracerebral hemorrhage (ICH) is a disease associated with high mortality, disability, and dysfunction (Qureshi et al, 2001). We used data mining and data analysis techniques to screen differentially expressed genes (DEGs) in perihematomal tissue (PH) and contralateral normal tissue of ICH patients. These DEGs were intersected with the ferroptosis dataset to obtain ferroptosis DEGs. to identify crucial biomarkers and establish the pathogenesis of ICH at the molecular level, we investigated key miRNAs and lncRNAs that may play principal roles in ICH. This dataset was used for further analysis and mining In this experiment, the microarray data of 11 samples, including perihematomal tissue (PH) and the corresponding contralateral white and gray matter, were obtained from public databases, so the consent of patients and ethics committee approval were unnecessary. The difference was statistically significant at the level of P < 0.05

RESULTS

DISCUSSION

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