2. Academic Validation
  3. Elevated SLC3A2 Expression Promotes the Progression of Gliomas and Enhances Ferroptosis Resistance through the AKT/NRF2/GPX4 Axis

Elevated SLC3A2 Expression Promotes the Progression of Gliomas and Enhances Ferroptosis Resistance through the AKT/NRF2/GPX4 Axis

  • Cancer Res Treat. 2025 Mar 10. doi: 10.4143/crt.2024.933.
Yuqian Zheng 1 2,  Shaolong Zhou 1,  Yiran Tao 1 2,  Zimin Shi 1 2,  Xiang Li 1 2,  Xudong Fu 1,  Jian Ma 1,  Weihua Hu 1,  Wulong Liang 1,  Xinjun Wang 1 2 3 4 5
Affiliations

Affiliations

  • 1 The Fifth Affiliated Hospital of Zhengzhou University, Department of Neurosurgery, Zhengzhou, Henan, China.
  • 2 The Third Affiliated Hospital of Zhengzhou University, Department of Neurosurgery, Zhengzhou, Henan, China.
  • 3 Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan, China.
  • 4 Maternal and Child Neurological Disorders International Joint Research Center, Zhengzhou, Henan, China.
  • 5 Tianjian Laboratory of Advanced Biomedical Sciences, School of life sciences, Zhengzhou University, Zhengzhou, Henan, China.
PMID: 40083086 DOI: 10.4143/crt.2024.933
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.

Keywords

Ferroptosis; Glioma; SLC3A2; Therapeutic sensitivity.

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