Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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.
Oncogene. 2024 Nov;43(45):3335-3347. doi: 10.1038/s41388-024-03173-3. Epub 2024 Sep 21.
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.
高级别浆液性卵巢癌（HGSOC）是一种侵袭性很强的疾病，常对当前的治疗方法产生耐药性，因此需要新的治疗策略。我们的研究确定 SGK1 是 PI3K 通路中的一个关键效应因子，作为一种有前途的治疗靶点，可以利用铁过载和脂质过氧化诱导的一种独特的细胞死亡形式——铁死亡。重要的是，SGK1 的激活，无论是通过高表达还是组成型激活的 SGK1-S422D 突变，都会使 HGSOC 对铁死亡产生耐药性。相反，SGK1 抑制显著增强了对铁死亡的敏感性，表现为 PTGS2 表达（铁死亡标志物）、脂质过氧化和无毒铁水平的增加。值得注意的是，这种增强的细胞毒性可被 ferrostatine-1 和铁螯合剂 deferoxamine 逆转，突出了脂质过氧化和铁失调在该过程中的关键作用。在机制上，SGK1 通过 NRF2 依赖途径保护 HGSOC 细胞免受铁死亡，促进谷胱甘肽合成和铁稳态，以及通过 mTOR/SREBP1/SCD1 介导的脂肪生成的 NRF2 非依赖途径。值得注意的是，药理学抑制 SGK1 使 HGSOC 异种移植模型对铁死亡诱导敏感，突出了其治疗潜力。这些发现确立了 SGK1 作为铁死亡的关键调节剂，并表明靶向 SGK1 联合铁死亡途径可能是 HGSOC 患者的一种潜在治疗策略。
