青岛大学Hong Jiang等研究人员合作发现 ，由FTH介导的铁稳态失调增加TP53突变性胶质母细胞瘤的铁死亡敏感性。相关论文于2024年12月12日在线发表在《神经科学通报》杂志上。

通过TCGA数据库分析，研究人员揭示了胶质母细胞瘤（GBM）中铁稳态的不平衡。TP53突变破坏了GBM中的铁稳态，表现为总铁水平升高和铁蛋白（FTH）减少。TP53突变引发的功能获得效应通过上调搔痒E3泛素蛋白连接酶（ITCH）蛋白在星形胶质细胞中的表达，导致FTH降解并增加游离铁水平。

TP53突变的星形胶质细胞对外源性柠檬酸铁铵（FAC）诱导的高铁环境具有更强的耐受性，但细胞内游离铁的增加使其对Erastin诱导的铁死亡更为敏感。值得注意的是，研究人员发现Erastin与FAC联合治疗显著增强了铁死亡。研究结果为从铁代谢角度开发针对TP53突变GBM患者的新药物和治疗方案提供了新的见解。

据了解，铁代谢是肿瘤发生和发展的关键因素。尽管TP53突变在GBM中较为常见，但TP53如何调节铁代谢的机制仍不明确。

附：英文原文

Title: Dysregulation of Iron Homeostasis Mediated by FTH Increases Ferroptosis Sensitivity in TP53-Mutant Glioblastoma

Author: Huan, Xuejie, Li, Jiangang, Chu, Zhaobin, Zhang, Hongliang, Cheng, Lei, Lun, Peng, Du, Xixun, Chen, Xi, Jiao, Qian, Jiang, Hong

Issue&Volume: 2024-12-12

Abstract: Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.

DOI: 10.1007/s12264-024-01322-y

Source: https://link.springer.com/article/10.1007/s12264-024-01322-y