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Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response

Xiao, Man-Yu, Pei, Wen-Jing, Li, Si, Li, Fang-Fang, Xie, Peng, Luo, Hao-Tian, Hyun Yoo, Hye, Piao, Xiang-Lan·2024·Bioorganic Chemistry
DOI 10.1016/j.bioorg.2024.107539
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Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor…

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Metadata

Authors
Xiao, M.-Y., Pei, W.-J., Li, S., Li, F.-F., Xie, P., Luo, H.-T., Hyun Yoo, H., & Piao, X.-L.
Venue
Bioorganic Chemistry
Publisher
Elsevier BV
Published
2024-09
Volume
150
Pages
107539
ISSN
0045-2068
DOI
10.1016/j.bioorg.2024.107539
Cited by
26
References
5
Language
en
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