Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathway
IntroductionCerebral ischemia–reperfusion (IR) causes severe secondary brain injury. Previous studies have demonstrated that ferroptosis is involved in IR-induced brain injury. However, whether IR induces ferroptosis in brain microvascular endothelial cells (BMVECs) is not fully understood.Materials...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2024.1504114/full |
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| author | Jiejie Hu Lijun Qin Guoqiang Zhu Jingjing Ren Hongxia Wang Jing Jin Haixue Zheng Dan Li Zhaoming Ge |
| author_facet | Jiejie Hu Lijun Qin Guoqiang Zhu Jingjing Ren Hongxia Wang Jing Jin Haixue Zheng Dan Li Zhaoming Ge |
| author_sort | Jiejie Hu |
| collection | DOAJ |
| description | IntroductionCerebral ischemia–reperfusion (IR) causes severe secondary brain injury. Previous studies have demonstrated that ferroptosis is involved in IR-induced brain injury. However, whether IR induces ferroptosis in brain microvascular endothelial cells (BMVECs) is not fully understood.Materials and methodsOxygen–glucose deprivation/reoxygenation (OGDR) was performed in bEND.3 cells to mimic IR injury in vitro, and a focal cerebral IR model was created in C57BL/6 mice. Transcriptomic sequencing of the cells was performed first, followed by bioinformatics analysis. Differentially expressed gene (DEG) enrichment analysis highlighted ferroptosis-related pathways.ResultsUsing Venn analysis, nine ferroptosis-related DEGs were identified, namely, Slc3a2, Slc7a11, Ccn2, Tfrc, Atf3, Chac1, Gch1, Lcn2, and Sesn2. Protein–protein interaction (PPI) analysis combined with molecular complex detection (MCODE) identified six hub genes, namely, Ddit3, Atf3, Sesn2, Trib3, Ppp1r15a, and Gadd45a. Spearman’s correlation analysis revealed a significant correlation between the hub genes and ferroptosis-related DEGs. After reperfusion, the levels of ferroptosis indicators were elevated, and the expression of the ferroptosis-related proteins Xc− and GPX4 decreased. SESN2 is a hub gene and key antioxidant regulator. SESN2 silencing reduced the expression of System Xc− and GPX4, whereas overexpression of SESN2 promoted the expression of System Xc− and GPX4.DiscussionThese results suggest that SESN2 is a negative regulator of ferroptosis. Enhancing the expression of SESN2 can alleviate ferroptosis through the activation of the System Xc−/GPX4 pathway. By integrating bioinformatics analysis with mechanistic exploration, this study revealed that ferroptosis plays a crucial role in IR-induced BMVECs injury, with SESN2 acting as a negative regulator via the System Xc−/GPX4 pathway. |
| format | Article |
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| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-e77eba92bb414f868d967b0f693f6d072025-01-29T06:46:17ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-01-011510.3389/fgene.2024.15041141504114Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathwayJiejie Hu0Lijun Qin1Guoqiang Zhu2Jingjing Ren3Hongxia Wang4Jing Jin5Haixue Zheng6Dan Li7Zhaoming Ge8Department of Neurology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, ChinaDepartment of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, ChinaSchool of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou, ChinaState Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaDepartment of Internal Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, ChinaDepartment of Neurology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, ChinaState Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaState Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaDepartment of Neurology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, ChinaIntroductionCerebral ischemia–reperfusion (IR) causes severe secondary brain injury. Previous studies have demonstrated that ferroptosis is involved in IR-induced brain injury. However, whether IR induces ferroptosis in brain microvascular endothelial cells (BMVECs) is not fully understood.Materials and methodsOxygen–glucose deprivation/reoxygenation (OGDR) was performed in bEND.3 cells to mimic IR injury in vitro, and a focal cerebral IR model was created in C57BL/6 mice. Transcriptomic sequencing of the cells was performed first, followed by bioinformatics analysis. Differentially expressed gene (DEG) enrichment analysis highlighted ferroptosis-related pathways.ResultsUsing Venn analysis, nine ferroptosis-related DEGs were identified, namely, Slc3a2, Slc7a11, Ccn2, Tfrc, Atf3, Chac1, Gch1, Lcn2, and Sesn2. Protein–protein interaction (PPI) analysis combined with molecular complex detection (MCODE) identified six hub genes, namely, Ddit3, Atf3, Sesn2, Trib3, Ppp1r15a, and Gadd45a. Spearman’s correlation analysis revealed a significant correlation between the hub genes and ferroptosis-related DEGs. After reperfusion, the levels of ferroptosis indicators were elevated, and the expression of the ferroptosis-related proteins Xc− and GPX4 decreased. SESN2 is a hub gene and key antioxidant regulator. SESN2 silencing reduced the expression of System Xc− and GPX4, whereas overexpression of SESN2 promoted the expression of System Xc− and GPX4.DiscussionThese results suggest that SESN2 is a negative regulator of ferroptosis. Enhancing the expression of SESN2 can alleviate ferroptosis through the activation of the System Xc−/GPX4 pathway. By integrating bioinformatics analysis with mechanistic exploration, this study revealed that ferroptosis plays a crucial role in IR-induced BMVECs injury, with SESN2 acting as a negative regulator via the System Xc−/GPX4 pathway.https://www.frontiersin.org/articles/10.3389/fgene.2024.1504114/fullferroptosisischemia/reperfusionbrain microvascular endothelial cellsSESN2system Xc-RNA-seq |
| spellingShingle | Jiejie Hu Lijun Qin Guoqiang Zhu Jingjing Ren Hongxia Wang Jing Jin Haixue Zheng Dan Li Zhaoming Ge Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathway Frontiers in Genetics ferroptosis ischemia/reperfusion brain microvascular endothelial cells SESN2 system Xc- RNA-seq |
| title | Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathway |
| title_full | Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathway |
| title_fullStr | Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathway |
| title_full_unstemmed | Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathway |
| title_short | Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc−/GPX4 pathway |
| title_sort | based on bioinformatics sesn2 negatively regulates ferroptosis induced by ischemia reperfusion via the system xc gpx4 pathway |
| topic | ferroptosis ischemia/reperfusion brain microvascular endothelial cells SESN2 system Xc- RNA-seq |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1504114/full |
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