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

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

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.661663

DOI=10.3389/fnins.2021.661663

ISSN=1662-453X

ABSTRACT=<p>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: <italic>MAPK1</italic>, <italic>MAPK8</italic>, <italic>TNFAIP3</italic>, <italic>ATF4</italic>, and <italic>SLC2A1</italic>. Moreover, <italic>MAPK1</italic> 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 <italic>MAPK1</italic>-related molecules included <italic>hsa-miR-15b-5P</italic>, <italic>hsa-miR-93-5P</italic>, <italic>miR-20b-5p</italic>, <italic>SNHG16</italic>, <italic>XIST</italic>, <italic>AC084219.4</italic>, <italic>RP11-379K17.11</italic>, <italic>CTC-444N24.11</italic>, <italic>GS1-358P8.4</italic>, <italic>CTB-89H12.4</italic>, <italic>RP4-773N10.5</italic>, and <italic>FGD5-AS1.</italic> 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 <italic>MAPK1</italic>, <italic>ATF4</italic>, <italic>SLC2A1</italic>, and <italic>TNFAIP3</italic> were upregulated, whereas <italic>MAPK8</italic> was downregulated. Treadmill training increased the expression of anti-inflammatory molecules <italic>TNFAIP3</italic> and <italic>SLC2A1</italic> and reduced the expression of <italic>MAPK1, ATF4</italic>, and <italic>MAPK8</italic>, indicating that treadmill training may be utilized as antioxidant therapy to decrease neuronal ferroptosis. The results of this study indicated that the <italic>MAPK1</italic>-related mRNA–miRNA–lncRNA interaction chain could be potentially employed as a biomarker of the inception and progression of ferroptosis after cerebral hemorrhage.</p>