Dysregulation of Iron Homeostasis Mediated by FTH Increases Ferroptosis Sensitivity in TP53-Mutant Glioblastoma.
10.1007/s12264-024-01322-y
- Author:
Xuejie HUAN
1
;
Jiangang LI
1
;
Zhaobin CHU
2
;
Hongliang ZHANG
3
;
Lei CHENG
3
;
Peng LUN
3
;
Xixun DU
1
;
Xi CHEN
1
;
Qian JIAO
4
;
Hong JIANG
5
Author Information
1. Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
2. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China.
3. Department of Neurosurgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
4. Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China. jiaoqian@qdu.edu.cn.
5. Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China. jianghong@uor.edu.cn.
- Publication Type:Journal Article
- Keywords:
TP53 mutation;
Erastin;
Ferroptosis;
Glioblastoma;
Iron metabolism
- MeSH:
Ferroptosis/drug effects*;
Humans;
Iron/metabolism*;
Glioblastoma/metabolism*;
Tumor Suppressor Protein p53/metabolism*;
Homeostasis/physiology*;
Ferritins/metabolism*;
Brain Neoplasms/genetics*;
Mutation;
Astrocytes/drug effects*;
Cell Line, Tumor;
Piperazines/pharmacology*;
Quaternary Ammonium Compounds/pharmacology*;
Ferric Compounds
- From:
Neuroscience Bulletin
2025;41(4):569-582
- CountryChina
- Language:English
-
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.
