Mechanisms of dihydromyricetin against hepatocellular carcinoma elucidated by network pharmacology combined with experimental validation

Pharm Biol. 2023 Dec;61(1):1108-1119. doi: 10.1080/13880209.2023.2234000.

Abstract

Context: Dihydromyricetin (DMY) is extracted from vine tea, a traditional Chinese herbal medicine with anti-cancer, liver protection, and cholesterol-lowering effects.

Objective: This study investigated the mechanism of DMY against hepatocellular carcinoma (HCC).

Materials and methods: Potential DMY, HCC, and cholesterol targets were collected from relevant databases. PPI networks were created by STRING. Then, the hub genes of co-targets, screened using CytoHubba. GO and KEGG pathway enrichment, were performed by Metascape. Based on the above results, a series of in vitro experiments were conducted by using 40-160 μM DMY for 24 h, including transwell migration/invasion assay, western blotting, and Bodipy stain assay.

Results: Network pharmacology identified 98 common targets and 10 hub genes of DMY, HCC, and cholesterol, and revealed that the anti-HCC effect of DMY may be related to the positive regulation of lipid rafts. Further experiments confirmed that DMY inhibits the proliferation, migration, and invasion of HCC cells and reduces their cholesterol levels in vitro. The IC50 is 894.4, 814.4, 467.8, 1,878.8, 151.8, and 156.9 μM for 97H, Hep3B, Sk-Hep1, SMMC-7721, HepG2, and Huh7 cells, respectively. In addition, DMY downregulates the expression of lipid raft markers (CAV1, FLOT1), as well as EGFR, PI3K, Akt, STAT3, and Erk.

Discussion and conclusion: The present study reveals that DMY suppresses EGFR and its downstream pathways by reducing cholesterol to disrupt lipid rafts, thereby inhibiting HCC, which provides a promising candidate drug with low toxicity for the treatment of HCC.

Keywords: Cholesterol; hepatocellular carcinoma cells; lipid raft.

MeSH terms

  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / metabolism
  • ErbB Receptors
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / metabolism
  • Network Pharmacology

Substances

  • dihydromyricetin
  • ErbB Receptors

Grants and funding

This work was supported by the National Natural Sciences Foundation of China (grant numbers 82274159, 81973668 and 81774130), the National Science Fund of Hunan Province (grant number 2022JJ80088), the Key Project of the Educational Department of Hunan Province (grant numbers 20A375, 21A0226), Open Fund of the State Key Laboratory Cultivation Base Co-constructed by the Ministry of Traditional Chinese Medicine Powder and Innovative Drug Research in Hunan Province (grant number 21PTKF1004), the Scientific Research Project of Changsha Science and Technology Bureau (grant number kq2004060), Key Project of Hunan Provincial Health Commission (grant number 202213055529), Pharmaceutical Open Fund of Domestic First-class Disciplines (cultivation) of Hunan Province (grant number 2021YX07), the Graduate Research innovation project of Hunan University of Chinese Medicine (grant number 2021CX48), the innovation project of university students in Hunan University of Chinese Medicine (grant number No 136), Hunan College Students Innovation and Entrepreneurship Training Program Support Project (grant number S202110541072), the Youth Project of Natural Science Foundation of Hunan Province (grant number 2023JJ40485), the Youth Project of Educational Department of Hunan Province (grant number 22B0355), the Special Scientific and Technological Project for the Comprehensive Utilization of Ampelopsis grossedentata Resources of Hunan Qiankun Biotechnology Co., Ltd. and the First-Class Discipline of Pharmaceutical Science of Hunan.