NeuroD4 converts glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 antioxidant axis

  • Cell Death Discov. 2023 Aug 15;9(1):297. doi: 10.1038/s41420-023-01595-8.
Hao Wang  1  2 ,  Peiqi Zhao  1  2 ,  Ying Zhang  1  2 ,  Zhen Chen  1  2 ,  Han Bao  1  2 ,  Wenqi Qian  1  2 ,  Jian Wu  1  2 ,  Zhenqiu Xing  1  2 ,  Xiaowei Hu  1  2 ,  Kunlin Jin  3 ,  Qichuan Zhuge  4  5 ,  Jianjing Yang  6  7
Affiliations
  • 1. Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 2. Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 3. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
  • 4. Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. [email protected].
  • 5. Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. [email protected].
  • 6. Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. [email protected].
  • 7. Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. [email protected].
PMID: 37582760 DOI: 10.1038/s41420-023-01595-8
Abstract

Cell fate and proliferation ability can be transformed through reprogramming technology. Reprogramming glioblastoma cells into neuron-like cells holds great promise for glioblastoma treatment, as it induces their terminal differentiation. NeuroD4 (Neuronal Differentiation 4) is a crucial transcription factor in neuronal development and has the potential to convert astrocytes into functional neurons. In this study, we exclusively employed NeuroD4 to reprogram glioblastoma cells into neuron-like cells. In vivo, the reprogrammed glioblastoma cells demonstrated terminal differentiation, inhibited proliferation, and exited the cell cycle. Additionally, NeuroD4 virus-infected xenografts exhibited smaller sizes compared to the GFP group, and tumor-bearing mice in the GFP+NeuroD4 group experienced prolonged survival. Mechanistically, NeuroD4 overexpression significantly reduced the expression of SLC7A11 and Glutathione Peroxidase 4 (GPX4). The Ferroptosis inhibitor ferrostatin-1 effectively blocked the NeuroD4-mediated process of neuron reprogramming in glioblastoma. To summarize, our study demonstrates that NeuroD4 overexpression can reprogram glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 signaling pathway, thus offering a potential novel therapeutic approach for glioblastoma.

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