AbstractHigh-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.

摘要高度浆液性卵巢癌（HGSOC）是一种高度侵袭性的疾病，通常对目前的治疗产生耐药性，因此需要新的治疗策略。我们的研究确定了PI3K途径中的关键效应子SGK1是利用铁上睑下垂（一种由铁超载和脂质过氧化诱导的细胞死亡的独特形式）的有希望的治疗靶点。

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.

重要的是，SGK1激活，无论是通过高表达还是组成型活性SGK1-S422D突变，都会赋予HGSOC对铁浓化的抗性。相反，SGK1抑制显着增强了对ferroptosis的敏感性，如PTGS2表达增加（ferroptosis标记），脂质过氧化和有毒游离铁水平所示。

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.

值得注意的是，这种增强的细胞毒性被ferrostatin-1和铁螯合剂去铁胺逆转，突出了脂质过氧化和铁失调在该过程中的关键作用。从机制上讲，SGK1通过NRF2依赖性途径保护HGSOC细胞免于铁浓化，促进谷胱甘肽合成和铁稳态，并通过mTOR/SREBP1/SCD1介导的脂肪生成促进NRF2非依赖性途径。

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..

值得注意的是，药理学SGK1抑制使HGSOC异种移植模型对ferroptosis诱导敏感，突出了其治疗潜力。这些发现将SGK1确立为ferroptosis的关键调节剂，并建议将SGK1与ferroptosis途径一起作为HGSOC患者的潜在治疗策略。。

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Fig. 1: HGSOC cells with high SGK1 expression are resistant to ferroptosis-inducing agents.Fig. 2: Oncogenic activation of SGK1 confers resistance to ferroptosis.Fig. 3: Activation of SGK1 suppresses ferroptosis through induction of NRF2 expression.Fig. 4: Inhibition of SGK1-NRF2 signaling axis promotes ferroptosis via suppressing SLC7A11-mediated GSH synthesis and impairing iron homeostasis.Fig.

图1：具有高SGK1表达的HGSOC细胞对ferroptosis诱导剂具有抗性。。图3:SGK1的激活通过诱导NRF2表达抑制ferroptosis。图4:SGK1-NRF2信号轴的抑制通过抑制SLC7A11介导的GSH合成和损害铁稳态来促进铁浓化。图。

5: Targeting SGK1 sensitizes HGSOC cells to ferroptosis inducer through inhibiting SREBP/SCD1.Fig. 6: Targeting SGK1 sensitizes HGSOC to ferroptosis inducer in vivo.Fig. 7: Proposed model of SGK1 suppressing ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways..

5： 靶向SGK1通过抑制SREBP/SCD1使HGSOC细胞对ferroptosis诱导剂敏感。图6：靶向SGK1使HGSOC在体内对ferroptosis诱导剂敏感。图7:SGK1通过NRF2依赖性和非依赖性途径抑制卵巢癌铁浓化的拟议模型。。

Data availability

数据可用性

The data generated in this study are available upon request from the corresponding author.

。

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Download referencesFundingThis work was supported by the National Natural Science Foundation of China (No. 82472708, 82372649, and 82302981), Zhejiang Provincial Natural Science Foundation of China (LY24H160028), Medicine and Health Technology Program of Zhejiang Province (2024KY1255), Discipline Cluster of Oncology, Wenzhou Medical University, China (z2-2023015), and Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation (2018E10008).Author informationAuthor notesThese authors contributed equally: Xiaolin Sang, Jiaxin Han.Authors and AffiliationsZhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaXiaolin Sang, Weiji Cai, Zhijie Yu & Pixu LiuCancer 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, ChinaJiaxin Han, Zhaojing Wang, Xingming Liao, Zhuolin Kong & Hailing ChengAuthorsXiaolin SangView author publicationsYou can also search for this author in.

下载参考文献资助这项工作得到了国家自然科学基金（编号8247270882372649和82302981），浙江省自然科学基金（LY24H160028），浙江省医药卫生技术计划（2024KY1255），温州医科大学肿瘤学学科群（z2-2023015）和浙江省智能癌症生物标志物发现与翻译重点实验室（2018E10008）的支持。作者信息作者注意到这些作者做出了同样的贡献：桑晓林，韩嘉欣。作者和附属机构温州医科大学附属第一医院智能癌症生物标志物发现与翻译重点实验室，浙江温州，中国桑晓林，蔡伟基，余志杰和刘皮旭癌症研究所，大连分子靶向癌症治疗重点实验室，大连医科大学第二医院；。

PubMed Google ScholarJiaxin HanView author publicationsYou can also search for this author in

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PubMed Google ScholarZhaojing WangView author publicationsYou can also search for this author in

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PubMed Google ScholarWeiji CaiView作者出版物您也可以在

PubMed Google ScholarXingming LiaoView author publicationsYou can also search for this author in

PubMed谷歌学者廖兴明查看作者出版物您也可以在

PubMed Google ScholarZhuolin KongView author publicationsYou can also search for this author in

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PubMed Google ScholarZhijie YuView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsPL, HC, and ZY conceived and designed the study and drafted the manuscript. XS and JH performed most of the experiments, collected and analyzed the data. XS, JH, and ZW performed the flow cytometric analysis. XS, WC, and ZW performed quantitative RT-PCR analysis and IHC staining.

PubMed Google ScholarContributionsPL，HC和ZY构思并设计了这项研究并起草了手稿。XS和JH进行了大部分实验，收集并分析了数据。XS，JH和ZW进行了流式细胞术分析。XS，WC和ZW进行了定量RT-PCR分析和IHC染色。

XS and WC performed animal experiments. XL and ZK performed clinical data analysis. All authors revised and approved the manuscript.Corresponding authorsCorrespondence to.

XS和WC进行了动物实验。XL和ZK进行了临床数据分析。所有作者都修改并批准了手稿。通讯作者通讯。

Zhijie Yu, Hailing Cheng or Pixu Liu.Ethics declarations

余志杰、程海玲或刘丕旭。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval

道德认可

The animal study was approved by the Institutional Animal Care and Use Committee of the First Affiliated Hospital of Wenzhou Medical University (Approval No. WYYY-IACUC-AEC-2023-083). All methods were performed in accordance with the relevant guidelines and regulations.

该动物研究经温州医科大学第一附属医院机构动物护理和使用委员会批准（批准号：WYYY-IACUC-AEC-2023-083）。所有方法均按照相关指南和规定进行。

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Additional informationPublisher的注释Springer Nature在已发布地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息权利和许可Pringer Nature或其许可方（例如协会或其他合作伙伴）根据与作者或其他权利持有人的出版协议对本文拥有专有权；本文接受稿件版本的作者自行存档仅受此类出版协议和适用法律的条款管辖。转载和许可本文引用本文Sang，X.，Han，J.，Wang，Z。

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

SGK1通过NRF2依赖性和非依赖性途径抑制卵巢癌的ferroptosis。。

Oncogene (2024). https://doi.org/10.1038/s41388-024-03173-3Download citationReceived: 18 January 2024Revised: 06 September 2024Accepted: 16 September 2024Published: 21 September 2024DOI: https://doi.org/10.1038/s41388-024-03173-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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