Department of Pediatrics, First Affiliated Hospital of Hebei Medical University, Hebei Medical University, Shijiazhuang 050000, China.
Institute for Epidemic Disease Control, Shijiazhuang Center for Disease Control and Prevention, Shijiazhuang 050000, China.
Cells. 2022 Nov 25;11(23):3778. doi: 10.3390/cells11233778.
The mechanisms underlying ferroptosis in neonatal hypoxic-ischemic brain damage (HIBD) remain unclear.
Four microarray datasets were collected from the GEO database (three mRNA datasets GSE23317, GSE144456, and GSE112137, and one miRNA microarray dataset GSE184939). Weighted gene co-expression network analysis (WGCNA) was used to identify modules of HIBD-related genes. The ferroptosis-related genes were extracted from FerrDb, of which closely correlated to HIBD were obtained after the intersection with existing HIBD's DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as protein-protein interaction (PPI) network analysis were subsequently conducted. Cytoscape was used to identify central genes. Immune cell infiltration analysis was performed by the CIBERSORT algorithm.
Fifty-six ferroptosis-related differentially expressed genes (FRDEGs) were screened, mainly related to ferroptosis, autophagy, hypoxia response, metabolic pathways, and immune inflammation. The seven optimal hub FRDEGs were obtained by intersecting with key modules of WGCNA. Then, the expression levels of the seven optimal hub FRDEGs were validated in the GSE144456 and GSE112137 datasets, and the ferroptosis-related mRNA-miRNA network was established. In addition, this study revealed immune cell infiltration in the HIBD cerebral cortex and the interaction between immune cells. Moreover, notably, specific FRDEGs were strongly positively correlated with immune function.
The mechanism of ferroptosis is intricate and closely related to neonatal HIBD. Therefore, targeting ferroptosis-related gene therapy and immunotherapy may have therapeutic prospects for neonatal HIBD.
新生儿缺氧缺血性脑损伤（HIBD）中铁死亡的机制尚不清楚。
从 GEO 数据库中收集了四个微阵列数据集（三个 mRNA 数据集 GSE23317、GSE144456 和 GSE112137，以及一个 miRNA 微阵列数据集 GSE184939）。使用加权基因共表达网络分析（WGCNA）识别 HIBD 相关基因模块。从 FerrDb 中提取铁死亡相关基因，与现有的 HIBD 的 DEGs 进行交集后，获得与 HIBD 密切相关的基因。随后进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路富集分析，以及蛋白质-蛋白质相互作用（PPI）网络分析。Cytoscape 用于识别中心基因。通过 CIBERSORT 算法进行免疫细胞浸润分析。
筛选出 56 个铁死亡相关差异表达基因（FRDEGs），主要与铁死亡、自噬、缺氧反应、代谢途径和免疫炎症有关。通过与 WGCNA 的关键模块相交，获得了七个最佳枢纽 FRDEGs。然后，在 GSE144456 和 GSE112137 数据集验证了这七个最佳枢纽 FRDEGs 的表达水平，并建立了铁死亡相关的 mRNA-miRNA 网络。此外，本研究揭示了 HIBD 大脑皮质中的免疫细胞浸润和免疫细胞之间的相互作用。此外，值得注意的是，特定的 FRDEGs 与免疫功能呈强烈正相关。
铁死亡的机制复杂，与新生儿 HIBD 密切相关。因此，针对铁死亡相关基因治疗和免疫治疗可能为新生儿 HIBD 提供治疗前景。
