Based on bioinformatics, SESN2 negatively regulates ferroptosis induced by ischemia reperfusion via the System Xc-/GPX4 pathway

文献类型： 外文期刊

第一作者： Hu, Jiejie

作者： Hu, Jiejie;Jin, Jing;Ge, Zhaoming;Qin, Lijun;Zhu, Guoqiang;Ren, Jingjing;Zheng, Haixue;Li, Dan;Wang, Hongxia

作者机构：

关键词： ferroptosis; ischemia/reperfusion; brain microvascular endothelial cells; SESN2; system Xc-; RNA-seq; hub gene

期刊名称：FRONTIERS IN GENETICS （ 影响因子：2.8； 五年影响因子：3.3 ）

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年卷期： 2025 年 15 卷

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收录情况： SCI

摘要： Introduction Cerebral 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 methods Oxygen-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.Results Using 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.Discussion These 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.

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