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人参皂苷20(S)-Rg3上调鲨烯环氧酶以重编程卵巢癌细胞的胆固醇代谢。

Ginsenoside 20(S)-Rg3 upregulates SQLE to reprogram cholesterol metabolism of ovarian cancer cells.

作者信息

He Fang, Zhou Yuanyuan, Fu Jing, Chang ShiXue, Cui Xi, Feng Zhaozu, Zhao Le, Li Xu

机构信息

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.

Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.

出版信息

iScience. 2025 Jul 1;28(8):112853. doi: 10.1016/j.isci.2025.112853. eCollection 2025 Aug 15.

DOI:10.1016/j.isci.2025.112853
PMID:40792023
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12337702/
Abstract

Ginsenoside 20(S)-Rg3 exhibits the anti-ovarian cancer activity by modulating aerobic glycolysis, but its role in reprogramming sterol metabolism remains unclear. This research utilized transcriptomic and lipidomic to identify the key metabolic pathways and targets influenced by 20(S)-Rg3. 20(S)-Rg3 altered 175 mRNAs and 64 metabolites in ovarian cancer cells, and cluster analysis found that the differentially expressed genes and metabolites were highly associated with the steroid biosynthesis. Multi-omics analysis revealed squalene epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis, was upregulated by 20(S)-Rg3. Silencing of SQLE attenuated the inhibitory effects of 20(S)-Rg3 on ovarian cancer cell proliferation and , as well as cell migration, invasion, and cholesterol synthesis. 20(S)-Rg3 enhanced SQLE expression by downregulating HIF-1α. Co-immunoprecipitation confirmed the interaction between SQLE and farnesyl-diphosphate farnesyltransferase 1 (FDFT1), another rate-limiting enzyme in cholesterol metabolism. These findings suggest that 20(S)-Rg3 exerts anti-ovarian cancer effects by HIF-1α/SQLE/FDFT1 to reprogram cholesterol metabolism.

摘要

人参皂苷20(S)-Rg3通过调节有氧糖酵解发挥抗卵巢癌活性，但其在重编程甾醇代谢中的作用仍不清楚。本研究利用转录组学和脂质组学来确定受20(S)-Rg3影响的关键代谢途径和靶点。20(S)-Rg3改变了卵巢癌细胞中的175个mRNA和64种代谢物，聚类分析发现差异表达的基因和代谢物与类固醇生物合成高度相关。多组学分析显示，类固醇生物合成中的限速酶角鲨烯环氧酶（SQLE）被20(S)-Rg3上调。沉默SQLE可减弱20(S)-Rg3对卵巢癌细胞增殖以及细胞迁移、侵袭和胆固醇合成的抑制作用。20(S)-Rg3通过下调HIF-1α增强SQLE表达。免疫共沉淀证实了SQLE与法尼基二磷酸法尼基转移酶1（FDFT1）之间的相互作用，FDFT1是胆固醇代谢中的另一种限速酶。这些发现表明，20(S)-Rg3通过HIF-1α/SQLE/FDFT1重编程胆固醇代谢发挥抗卵巢癌作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/80b1cafae8ef/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/5256d9debbcc/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/e41560090f7a/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/f54f830ed4a5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/fc014ee8b4c6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/aebac57267c0/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/cb8c1dac2821/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/d1d84a5a914d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/9c8bd51179e7/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/501b3a382c9d/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/80b1cafae8ef/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/5256d9debbcc/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/e41560090f7a/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/f54f830ed4a5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/fc014ee8b4c6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/aebac57267c0/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/cb8c1dac2821/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/d1d84a5a914d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/9c8bd51179e7/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/501b3a382c9d/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6788/12337702/80b1cafae8ef/gr9.jpg

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[9]
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[10]
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本文引用的文献

[1]
20(S)-ginsenoside Rg3 suppresses gastric cancer cell proliferation by inhibiting E2F-DP dimerization.

Phytomedicine. 2025-6

[2]
SQLE-catalyzed squalene metabolism promotes mitochondrial biogenesis and tumor development in K-ras-driven cancer.

Cancer Lett. 2025-4-28

[3]
Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis.

Adv Sci (Weinh). 2025-3

[4]
Disturbing Cholesterol/Sphingolipid Metabolism by Squalene Epoxidase Arises Crizotinib Hepatotoxicity.

Adv Sci (Weinh). 2025-4

[5]
Metabolic Signaling in Cancer Metastasis.

Cancer Discov. 2024-6-3

[6]
Ginseng polysaccharides ameliorate ulcerative colitis via regulating gut microbiota and tryptophan metabolism.

Int J Biol Macromol. 2024-4

[7]
Ginsenoside 20(S)-Rg3 reduces expression and promotes CDC25A proteasomal degradation in epithelial ovarian cancer.

J Ginseng Res. 2024-1

[8]
Rare ginsenosides: A unique perspective of ginseng research.

J Adv Res. 2024-12

[9]
Physical exercise reverses immuno-cold tumor microenvironment via inhibiting SQLE in non-small cell lung cancer.

Mil Med Res. 2023-8-18

[10]
Role of exosomes in transferring chemoresistance through modulation of cancer glycolytic cell metabolism.

Cytokine Growth Factor Rev. 2023-10

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