文献类型：期刊文献

英文题名：Targeting EZH2-driven cholesterol metabolic vulnerability through Napabucasin suppresses ovarian cancer metastasis

作者：Ma, Mingjun[1];Wang, Chao[1];Zhang, Yue[1];Cheng, Shanshan[1];Yang, Jiani[1];Zou, Yejun[1];Tian, Xiu[1];Gu, Sijia[1];Li, Jianxiao[1];Cao, Weiwei[1];Huang, Chao[1];Shao, Yaodi[1];Zhao, Yaqian[1];Gao, Yutong[1];Liu, Yilin[1];Pang, Wen[1];Shi, Shuo[1];Ding, Hui[1];Zhang, Minghai[1];Cai, Yifei[1];Wu, Yongsong[1];Xue, Renhao[1];Cheng, Xiawei[2];Chu, Chen[3];Sheng, Jindan[1];Wang, Yu[1]

机构：[1]Tongji Univ, Shanghai Matern & Infant Hosp 1,Dept Gynecol, Sch Med,Shanghai Inst Maternal Fetal Med & Gynecol, Clin & Translat Res Ctr,Shanghai Key Lab Maternal, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Optogenet & Synthet Biol Interdisciplinary Res Ctr, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Sch Pharm,State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[3]Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA

年份：2026

卷号：17

期号：1

外文期刊名：CELL DEATH & DISEASE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001808984300001)】；

基金：The work was supported by the National Natural Science Foundation of China (Grant No. 82303869 to JS, Grant No. 82072866, 82272888 to YW) and the Shanghai Sailing Program (Grant No. 23YF1433400 to JS). Shanghai Hospital Development Center Foundation (Grant No. SHDC12022106, 2022SKLY-12 to YW) and Shanghai Jiao Tong University (Grant No. YG2022ZD005 to YW), Shanghai First Maternity and Infant Hospital (Grant No. 2023B01,2023A01 to YW, 2022RC08 to JS), Health Commission of Shanghai Pudong District (Grant No. PWZxq2022-03, PW2023D-14 to YW).

语种：英文

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-kappa B-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.