2. Academic Validation
  3. 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone-nanoparticle regulation mechanism of basic transcription factor 3 through hypoxia inducible factor-1α ubiquitination mediation to inhibit human hepatoma cell proliferation

5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone-nanoparticle regulation mechanism of basic transcription factor 3 through hypoxia inducible factor-1α ubiquitination mediation to inhibit human hepatoma cell proliferation

  • Phytomedicine. 2025 Nov:147:157236. doi: 10.1016/j.phymed.2025.157236.
Jiaxin Chen 1,  Yixuan Wang 1,  Shuhan Wang 1,  Haoyi Cheng 1,  Dandan Wang 1,  Jinghao Fu 1,  Jinge Hao 1,  Jing Zhang 1,  Xuewu Zhang 2
Affiliations

Affiliations

  • 1 Medical College of Yanbian University, Jilin Province, China.
  • 2 Medical College of Yanbian University, Jilin Province, China. Electronic address: zhangxuewu@ybu.edu.cn.
PMID: 40939546 DOI: 10.1016/j.phymed.2025.157236
Abstract

Background: The main bioactive component of Sorbaria sorbifolia, 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone (TTF1), exhibits anti-cancer activity in human hepatoma cells. To improve its solubility, it can be prepared as nanoparticles (TTF1-NP), however, their role modulating BTF3/HIF-1α ubiquitination and its downstream glycolytic disruption remains unexplored.

Purpose: To explore the mechanism by which TTF1-NP inhibits the glycolysis and proliferation of hepatoma cells through BTF3-mediated HIF-1α ubiquitination.

Study design and methods: This study investigated TTF1-NP's anti-liver Cancer mechanism in vitro and vivo. Under hypoxia, TTF1-NP suppressed hepatoma cell proliferation and glycolysis via CCK-8, cloning, flow cytometry, and western blot. Proteomics and survival analysis linked BTF3 to liver Cancer progression. TTF1-NP downregulated BTF3, promoting HIF-1α ubiquitination to inhibit glycolysis, confirmed by overexpression/knockdown experiments. In mouse xenograft and rat primary liver Cancer models, TTF1-NP attenuated tumor growth, reduced glycolysis, and enhanced HIF-1α degradation, demonstrating its therapeutic potential.

Results: Under hypoxic, TTF1-NP inhibited hepatoma cell proliferation by inducing G0/G1 arrest. TTF1-NP treatment reduced lactate production, ATP, and glucose uptake, and significantly downregulated glycolytic Enzymes. It suppressed BTF3 (overexpressed in liver Cancer), promoting HIF-1α ubiquitination to block glycolysis and tumor growth. In vivo, TTF1-NP attenuated tumor progression, downregulated BTF3/HIF-1α, enhanced HIF-1α degradation, reduced hepatic radioconcentration and inflammation. Mechanistically, it disrupted BTF3-HIF-1α interaction, promoting HIF-1α ubiquitination and inhibiting glycolytic for antitumor effects.

Conclusion: TTF1-NP inhibites BTF3, promoting HIF-1α ubiquitination to suppress glycolysis and hepatoma growth, these results offer a novel dual-targeted anti-tumor strategy and lay a solid foundation for the development of S. sorbifolia and TTF1-NP as innovative anti-tumor candidate drugs.

Keywords

Basic transcription factor 3; Glycolysis; Hypoxia-inducible factor-1α; Liver cancer; Sorbaria sorbifolia.

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