Wang Zhao, Tian Jinjie, Wang Lei, Yan Hongyan, Feng Sujuan, Zhang Yi
Department of Neurosurgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
Department of Emergency Center, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
Mol Neurobiol. 2025 Jan;62(1):233-245. doi: 10.1007/s12035-024-04170-z. Epub 2024 Jun 4.
The pathogenesis of ferroptosis in traumatic brain injury (TBI) is unclear; therefore, we aimed to identify key molecules associated with ferroptosis in TBI using bioinformatics analysis to determine its underlying mechanisms. GSE128543 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and TBI-associated modules were obtained by weighted gene co-expression network analysis (WGCNA). We identified 60 differentially expressed genes (DEGs) by intersecting the modules with ferroptosis and glycolysis/gluconeogenesis gene libraries. The hypoxia-inducible factor-1 (HIF-1) signaling pathway was identified to be critical for ferroptosis post-TBI, and protein-protein interaction (PPI) network identified 20 hub genes, including phosphoglycerate kinase 1 (PGK1), ribosomal protein (RP) family, pyruvate kinase M1/2 (PKM), hypoxia-inducible factor 1α subunit (HIF-1α), and MYC genes. In this study, we further explored the role of PGK1, a gene involved in HIF-1 signaling pathway; however, its role and mechanism in TBI are still unclear. Moreover, we constructed a TBI mouse model and examined PGK1 and HIF-1α expression levels, and the results revealed their expressions increased after cortical injury in mice and they co-localized in the same cells. Furthermore, we examined the expressions of PGK1 in the cerebrospinal fluid of 20 clinical patients with different degrees of brain injuries within 48 h of surgery and examined the cognitive function of patients according to the Glasgow Coma Scale (GCS). The results revealed that PGK1 expression level was negatively correlated with the severity of the brain injury. These findings suggest that PGK1 may become a potential hub gene for ferroptosis via the HIF-1 signaling pathway, second to neurological injury after TBI, thereby affecting patient prognosis.
创伤性脑损伤（TBI）中铁死亡的发病机制尚不清楚；因此，我们旨在通过生物信息学分析确定与TBI中铁死亡相关的关键分子，以确定其潜在机制。从基因表达综合数据库（GEO）下载GSE128543数据集，并通过加权基因共表达网络分析（WGCNA）获得与TBI相关的模块。通过将这些模块与铁死亡和糖酵解/糖异生基因文库相交，我们鉴定出60个差异表达基因（DEG）。缺氧诱导因子-1（HIF-1）信号通路被确定为TBI后铁死亡的关键通路，蛋白质-蛋白质相互作用（PPI）网络鉴定出20个枢纽基因，包括磷酸甘油酸激酶1（PGK1）、核糖体蛋白（RP）家族、丙酮酸激酶M1/2（PKM）、缺氧诱导因子1α亚基（HIF-1α）和MYC基因。在本研究中，我们进一步探讨了参与HIF-1信号通路的基因PGK1的作用；然而，其在TBI中的作用和机制仍不清楚。此外，我们构建了TBI小鼠模型，检测了PGK1和HIF-1α的表达水平，结果显示它们在小鼠皮质损伤后的表达增加，且共定位于同一细胞中。此外，我们检测了20例不同程度脑损伤临床患者术后48小时内脑脊液中PGK1的表达，并根据格拉斯哥昏迷量表（GCS）评估患者的认知功能。结果显示，PGK1表达水平与脑损伤严重程度呈负相关。这些发现表明，PGK1可能通过HIF-1信号通路成为铁死亡的潜在枢纽基因，仅次于TBI后的神经损伤，从而影响患者预后。
