2. Academic Validation
  3. SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways

SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways

  • Oncogene. 2024 Sep 21. doi: 10.1038/s41388-024-03173-3.
Xiaolin Sang # 1,  Jiaxin Han # 2,  Zhaojing Wang 2,  Weiji Cai 1,  Xingming Liao 2,  Zhuolin Kong 2,  Zhijie Yu 3,  Hailing Cheng 4,  Pixu Liu 5
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 Cancer Institute, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, The Second Hospital of Dalian Medical University; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China.
  • 3 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. zhijie_yu@wzhospital.cn.
  • 4 Cancer Institute, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, The Second Hospital of Dalian Medical University; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China. hailingcheng_dmu@163.com.
  • 5 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. pixuliu@wmu.edu.cn.
  • # Contributed equally.
PMID: 39306614 DOI: 10.1038/s41388-024-03173-3
Abstract

High-grade serous ovarian Cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit Ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to Ferroptosis in HGSOC. Conversely, SGK1 inhibition significantly enhances sensitivity to Ferroptosis, as shown by increased PTGS2 expression (a Ferroptosis marker), lipid peroxidation, and toxic-free iron levels. Remarkably, this enhanced cytotoxicity is reversed by ferrostatin-1 and the iron chelator deferoxamine, highlighting the pivotal roles of lipid peroxidation and iron dysregulation in the process. Mechanistically, SGK1 protects HGSOC cells from Ferroptosis via NRF2-dependent pathways, promoting glutathione synthesis and iron homeostasis, and NRF2-independent pathways via mTOR/SREBP1/SCD1-mediated lipogenesis. Notably, pharmacological SGK1 inhibition sensitizes HGSOC xenograft models to Ferroptosis induction, highlighting its therapeutic potential. These findings establish SGK1 as a critical regulator of Ferroptosis and suggest targeting SGK1 alongside Ferroptosis pathways as a potential therapeutic strategy for HGSOC patients.

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