Subcellular redistribution of Rhein from whole cellular to single mitochondria for enhancing anti-hepatoma efficacy

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-12 DOI:10.1016/j.phymed.2025.156962

Ling-Ling Wu , Weihua Di , Litao Shao , Jie Zhou , Yu-Yu Qiu , Mengrui Zhang , Zhenye Li , Yanqun Zhang , Pengcheng Luan , Jifan Li , Gongchang Yu , Guiqian Fang , Caicai Meng , Bin Shi , Xuemei Zhao , Qixin Chen , Xintian Shao

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Abstract

Background

RECQL4 is a critical factor in DNA repair and serves as a significant biomarker for liver cancer. Inhibiting RECQL4 induces apoptosis in liver cancer cells. Given the role of mitochondria in regulating apoptosis and the dual localization of RECQL4 in both the mitochondria and nucleus, targeting mitochondrial RECQL4 may induce mitochondrial dysfunction, thereby enhancing the therapeutic efficacy of liver cancer treatments.

Purpose

Unlike traditional drug structure optimization, which focuses solely on protein target interactions, our approach optimizes drug structure based on both organelle distribution and protein interactions.

Methods

As a proof of concept, we selected Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), an auto-fluorescent, lipophilic anthraquinone found in a variety of different medicinal herbs used in TCM that is known to bind to RECQL4, a protein that is distributed throughout the cytosol, mitochondria, and other subcellular locations, albeit unevenly. Rhein has the tendency to accumulate in different subcellular organelles, which reduces the overall efficacy of the drug. To overcome this limitation, we conjugated a triphenylphosphonium group Rhein to direct the drug to the mitochondria, resulting in Rh-Mito.

Results

Our results demonstrated that this chemical modification retains the ability to intervene in the expression of RECQL4 protein while also improving the cellular uptake of Rh-Mito. Utilizing advanced imaging techniques, we show that Rh-Mito preferentially accumulated in the mitochondria, where it targeted RECQL4 to inhibit the repair of mtDNA, altered the morphology of mitochondrial cristae, and induced apoptosis. Notably, Rh-Mito displayed superior anti-tumor efficacy compared to unmodified Rhein.

Conclusion

Rh-Mito was designed to selectively target mitochondria, avoiding interactions with other organelles. This modification strengthens its binding to RECQL4, disrupts mitochondrial cristae, inhibits tumor cell migration, and promotes apoptosis, thereby improving its therapeutic efficacy in liver cancer treatment.

Abstract Image

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Rhein从全细胞到单个线粒体的亚细胞再分布增强抗肝癌疗效

recql4是DNA修复的关键因子，是肝癌的重要生物标志物。抑制RECQL4诱导肝癌细胞凋亡。考虑到线粒体在细胞凋亡中的调节作用，以及RECQL4在线粒体和细胞核中的双重定位，靶向线粒体RECQL4可能会诱导线粒体功能障碍，从而提高肝癌治疗的疗效。与传统药物结构优化仅关注蛋白质靶点相互作用不同，我们的方法基于细胞器分布和蛋白质相互作用来优化药物结构。为了验证这一概念，我们选择了Rhein（4,5-二羟基蒽醌-2-羧酸），这是一种自荧光、亲脂性蒽醌，存在于多种中药中，已知可以与RECQL4结合，RECQL4是一种分布在细胞质、线粒体和其他亚细胞位置的蛋白质，尽管不均匀。Rhein倾向于在不同的亚细胞器中积累，这降低了药物的整体功效。为了克服这一限制，我们偶联了一个三苯基磷酸基团莱茵，将药物引导到线粒体，从而产生Rh-Mito。结果表明，这种化学修饰保留了干预RECQL4蛋白表达的能力，同时也改善了Rh-Mito的细胞摄取。利用先进的成像技术，我们发现Rh-Mito优先积聚在线粒体中，在那里它靶向RECQL4抑制mtDNA的修复，改变线粒体嵴的形态，诱导细胞凋亡。值得注意的是，与未经修饰的Rhein相比，Rh-Mito显示出更好的抗肿瘤功效。结论rh - mito可选择性靶向线粒体，避免与其他细胞器相互作用。该修饰增强其与RECQL4的结合，破坏线粒体嵴，抑制肿瘤细胞迁移，促进细胞凋亡，从而提高其在肝癌治疗中的疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.