Dysregulation of Iron Homeostasis Mediated by FTH Increases Ferroptosis Sensitivity in TP53-Mutant Glioblastoma
Xuejie Huan1 · Jiangang Li1 · Zhaobin Chu3 · Hongliang Zhang4 · Lei Cheng4 · Peng Lun4 · Xixun Du1 · Xi Chen1 · Qian Jiao1 · Hong Jiang1,21 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 Qingdao Key Laboratory of Neurorehabilitation, University of Health and Rehabilitation Sciences, Qingdao 266113, China
3 College of Life Sciences, University of Chinese Academy of Sciences, Beijing 101408, China
4 Department of Neurosurgery, the Afliated Hospital of Qingdao University, Qingdao 266000, China
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.
Keywords
Glioblastoma; TP53 mutation; Iron metabolism; Ferroptosis; Erastin
