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<p>Ovarian cancer represents the most lethal gynecologic malignancy, with tumor metastasis being the primary contributor to patient mortality. EZH2, frequently overexpressed in various cancers, has been implicated in promoting metastatic progression through metabolic dysregulation. However, the mechanistic basis by which EZH2 reprograms cholesterol metabolism to facilitate ovarian cancer metastasis remains poorly defined. In this study, we demonstrated that EZH2 is highly expressed in both primary and metastatic ovarian cancer tissues, correlating positively with poor clinical prognosis. Genetic silencing of EZH2 significantly suppressed tumor proliferation and metastatic dissemination. Mechanistically, EZH2 overexpression activated the NF-κB-Rap1A signaling axis and orchestrated cholesterol metabolic reprogramming by activating SREBP2, while repressing TMED10, to promote ovarian cancer metastasis. Furthermore, we identified Napabucasin as a potent suppressor of EZH2/Rap1A axis and cholesterol metabolism. Notably, Napabucasin effectively inhibited ovarian cancer metastasis in vivo. Collectively, our findings elucidate a previously unrecognized mechanism by which EZH2 governs metastatic progression through cholesterol metabolic rewiring and propose Napabucasin as a promising therapeutic strategy for ovarian cancer, particularly in tumors with EZH2 hyperactivation.</p>

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Targeting EZH2-driven cholesterol metabolic vulnerability through Napabucasin suppresses ovarian cancer metastasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • Mingjun Ma,
  • Chao Wang,
  • Yue Zhang,
  • Shanshan Cheng,
  • Jiani Yang,
  • Yejun Zou,
  • Xiu Tian,
  • Sijia Gu,
  • Jianxiao Li,
  • Weiwei Cao,
  • Chao Huang,
  • Yaodi Shao,
  • Yaqian Zhao,
  • Yutong Gao,
  • Yilin Liu,
  • Wen Pang,
  • Shuo Shi,
  • Hui Ding,
  • Minghai Zhang,
  • Yifei Cai,
  • Yongsong Wu,
  • Renhao Xue,
  • Xiawei Cheng,
  • Chen Chu,
  • Jindan Sheng,
  • Yu Wang

摘要

Ovarian cancer represents the most lethal gynecologic malignancy, with tumor metastasis being the primary contributor to patient mortality. EZH2, frequently overexpressed in various cancers, has been implicated in promoting metastatic progression through metabolic dysregulation. However, the mechanistic basis by which EZH2 reprograms cholesterol metabolism to facilitate ovarian cancer metastasis remains poorly defined. In this study, we demonstrated that EZH2 is highly expressed in both primary and metastatic ovarian cancer tissues, correlating positively with poor clinical prognosis. Genetic silencing of EZH2 significantly suppressed tumor proliferation and metastatic dissemination. Mechanistically, EZH2 overexpression activated the NF-κB-Rap1A signaling axis and orchestrated cholesterol metabolic reprogramming by activating SREBP2, while repressing TMED10, to promote ovarian cancer metastasis. Furthermore, we identified Napabucasin as a potent suppressor of EZH2/Rap1A axis and cholesterol metabolism. Notably, Napabucasin effectively inhibited ovarian cancer metastasis in vivo. Collectively, our findings elucidate a previously unrecognized mechanism by which EZH2 governs metastatic progression through cholesterol metabolic rewiring and propose Napabucasin as a promising therapeutic strategy for ovarian cancer, particularly in tumors with EZH2 hyperactivation.