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

IF 8.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-09-08 DOI:10.1016/j.phymed.2025.157236

Jiaxin Chen, Yixuan Wang, Shuhan Wang, Haoyi Cheng, Dandan Wang, Jinghao Fu, Jinge Hao, Jing Zhang, Xuewu Zhang

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引用次数: 0

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.

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5,2',4'-三羟基-6,7,5'-三甲氧基黄酮纳米颗粒调控碱性转录因子3通过缺氧诱导因子-1α泛素化介导抑制人肝癌细胞增殖的机制。

背景：Sorbaria sorbiolia的主要生物活性成分5,2',4'-三羟基-6,7,5'-三甲氧基黄酮（TTF1）在人肝癌细胞中表现出抗癌活性。为了提高其溶解度，可以将其制备成纳米颗粒（TTF1-NP），然而，它们调节BTF3/HIF-1α泛素化及其下游糖酵解破坏的作用仍未被探索。目的：探讨TTF1-NP通过btf3介导的HIF-1α泛素化抑制肝癌细胞糖酵解和增殖的机制。研究设计和方法：研究TTF1-NP体外和体内抗肝癌机制。通过CCK-8、克隆、流式细胞术和western blot检测，TTF1-NP在缺氧条件下抑制肝癌细胞增殖和糖酵解。蛋白质组学和生存分析将BTF3与肝癌进展联系起来。TTF1-NP下调BTF3，促进HIF-1α泛素化，抑制糖酵解，通过过表达/敲低实验证实。在小鼠异种移植和大鼠原发性肝癌模型中，TTF1-NP抑制肿瘤生长，减少糖酵解，增强HIF-1α降解，显示其治疗潜力。结果：缺氧条件下，TTF1-NP通过诱导G0/G1阻滞抑制肝癌细胞增殖。TTF1-NP处理降低了乳酸生成、ATP和葡萄糖摄取，并显著下调糖酵解酶。抑制肝癌中过度表达的BTF3，促进HIF-1α泛素化，阻断糖酵解和肿瘤生长。在体内，TTF1-NP减缓肿瘤进展，下调BTF3/HIF-1α，增强HIF-1α降解，降低肝脏放射浓度和炎症。机制上，它破坏BTF3-HIF-1α相互作用，促进HIF-1α泛素化，抑制糖酵解，从而达到抗肿瘤作用。结论：TTF1-NP抑制BTF3，促进HIF-1α泛素化，抑制糖酵解和肝癌生长，这些结果提供了一种新的双靶向抗肿瘤策略，为sorbiolia和TTF1-NP作为创新抗肿瘤候选药物的发展奠定了坚实的基础。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.