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Original Article
- Elevated SLC3A2 Expression Promotes the Progression of Gliomas and Enhances Ferroptosis Resistance through the AKT/NRF2/GPX4 Axis
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Yuqian Zheng1,2
, Shaolong Zhou1, Yiran Tao1,2, Zimin Shi1,2, Xiang Li1,2, Xudong Fu1, Jian Ma1, Weihua Hu1, Wulong Liang1
, Xinjun Wang1,2,3,4,5
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DOI: https://doi.org/10.4143/crt.2024.933 [Accepted]
Published online: March 10, 2025
1The Fifth Affiliated Hospital of Zhengzhou University, Department of Neurosurgery, Zhengzhou, Henan, China
2The Third Affiliated Hospital of Zhengzhou University, Department of Neurosurgery, Zhengzhou, Henan, China
3Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
4Maternal and Child Neurological Disorders International Joint Research Center, Zhengzhou, Henan, China
5Tianjian Laboratory of Advanced Biomedical Sciences, School of life sciences, Zhengzhou University, Zhengzhou, Henan, China
2The Third Affiliated Hospital of Zhengzhou University, Department of Neurosurgery, Zhengzhou, Henan, China
3Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China
4Maternal and Child Neurological Disorders International Joint Research Center, Zhengzhou, Henan, China
5Tianjian Laboratory of Advanced Biomedical Sciences, School of life sciences, Zhengzhou University, Zhengzhou, Henan, China
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Corresponding author:
Wulong Liang
Email: fenghua880725@126.com
Xinjun Wang
Email: wangxj@zzu.edu.cn
Received: 26 September 2024 • Accepted: 7 March 2025
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Abstract
Purpose
The aim of this study is to determine the impact of SLC3A2 on the malignant phenotype of gliomas and its role in regulating ferroptosis sensitivity.
Materials and Methods
The malignant phenotype of glioma was assessed by cell proliferation assay, colony formation assay, EdU assay, wound healing and transwell experiments.We further validated the impact of reduced SLC3A2 expression on the sensitivity to ferroptosis in glioma cells through CCK-8 assays, flow cytometry, Western blotting, and transmission electron microscopy. Western blot was used to explore how SLC3A2 affects glioma sensitivity to ferroptosis through the AKT/NRF2/GPX4 axis. By establishing a subcutaneous xenograft tumor model in BALB/c-Nude mice, we investigated the growth of tumors following the knockout of SLC3A2 in glioma cells.
Results
Downregulation of SLC3A2 suppressed the malignant phenotype of glioma by blocking the cell cycle and EMT processes. On the other hand, loss of SLC3A2 not only downregulated SLC7A11 but also prevented the activation of the AKT/NRF2/GPX4 axis. These lead to increased accumulation of ROS and lipid peroxides, ultimately enhancing the susceptibility of glioma to ferroptosis.
Conclusion
Our findings suggest that SLC3A2 is an oncogene in gliomas, promoting their occurrence and development. It plays a critical role in ferroptosis resistance through the AKT/NRF2/GPX4 axis.
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