Ponicidin promotes ferroptosis to enhance treatment sensitivity in Lenvatinib-resistant hepatocellular carcinoma cells through regulation of KEAP1/NRF2

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-10 DOI:10.1016/j.phymed.2025.156824

Lisha Zhang , Hao Wang , Beibei Liang , Lijuan Qin , Mingzhu Zhang , Xingxian Lv , Shi Hu , Xiaoyu Fan , Wei Xie , Hao Yang , Gang Huang , Wei Jing , Jian Zhao

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Abstract

Objective

This study explores the therapeutic potential of Ponicidin on Lenvatinib-resistant hepatocellular carcinoma (HCC), elucidates its mechanism in reversing Lenvatinib resistance, and provides experimental evidence for its clinical application in overcoming this resistance.

Methods

Huh7 and HCC-LM3 cells were used to construct Lenvatinib-resistant cell lines, Huh7-LR and HCC-LM3-LR. Changes in the ferroptosis pathway post-drug resistance were observed by measuring ferroptosis-related markers. The proliferation assay were assessed by CCK-8, while the migration and invasion were measured by scratch and Transwell invasion assays. In mechanistic study, chip analysis and immunoprecipitation with biotin-labeled Ponicidin, were conducted to explore how Ponicidin overcame drug resistance. Xenograft model in nude mice was established to examine Ponicidin’s anti-HCC effects In vivo. Clinical specimens were used to assess the true status of patients in Lenvatinib-resistant HCC patients.

Results

Our study reveals for the first time that ferroptosis inhibition drives Lenvatinib resistance in HCC and identifies Ponicidin as a novel KEAP1-targeting agent to reverse this process. In vitro, ferroptosis pathway was suppressed in Lenvatinib-resistant cells. Ponicidin suppressed proliferation, clonogenicity, migration, and invasion in these cells. The combination of Ponicidin and Lenvatinib significantly inhibited proliferation and reversed drug resistance by activating the ferroptosis pathway. Preliminary mechanistic studies showed that Ponicidin binds to KEAP1, stabilizing the KEAP1/NRF2 interaction, inhibiting the nuclear translocation and activation of NRF2, and thereby inducing ferroptosis to overcome Lenvatinib resistance. In vivo, the combination of Ponicidin and Lenvatinib exhibited a synergistic effect, significantly delaying tumor growth. Clinically, p-NRF2 and GPX4 expression was higher in the Lenvatinib-insensitive group, suggesting that the ferroptosis pathway was inhibited in these patients. Thus, this study demonstrated that Ponicidin promotes ferroptosis to enhances treatment sensitivity in Lenvatinib-resistant HCC cells through KEAP1/NRF2.

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Ponicidin通过调节KEAP1/NRF2促进铁凋亡，提高lenvatinib耐药肝癌细胞的治疗敏感性

目的探讨Ponicidin对Lenvatinib耐药肝细胞癌（HCC）的治疗潜力，阐明其逆转Lenvatinib耐药的机制，为其临床应用提供实验依据。方法利用shuh7和HCC-LM3细胞构建lenvatinib耐药细胞株Huh7-LR和HCC-LM3- lr。通过测定铁中毒相关标志物，观察耐药后铁中毒途径的变化。CCK-8法检测细胞增殖，划痕法和Transwell法检测细胞迁移和侵袭。在机制研究中，通过芯片分析和生物素标记的Ponicidin免疫沉淀来探讨Ponicidin如何克服耐药。建立裸鼠异种移植瘤模型，观察其体内抗肝癌作用。临床标本用于评估lenvatinib耐药HCC患者的真实状态。我们的研究首次揭示了铁凋亡抑制在HCC中驱动Lenvatinib耐药，并鉴定了Ponicidin作为一种新的keap1靶向药物来逆转这一过程。在体外，lenvatinib耐药细胞中的铁下垂途径被抑制。poniciidin抑制这些细胞的增殖、克隆原性、迁移和侵袭。Ponicidin与Lenvatinib联用可激活铁下垂通路，显著抑制细胞增殖，逆转耐药。初步机制研究表明，Ponicidin与KEAP1结合，稳定KEAP1/NRF2相互作用，抑制NRF2的核易位和活化，从而诱导铁下沉，克服Lenvatinib耐药。在体内，Ponicidin和Lenvatinib联合使用表现出协同作用，显著延缓肿瘤生长。在临床上，lenvatinib不敏感组p-NRF2和GPX4的表达较高，表明这些患者的铁下垂途径受到抑制。因此，本研究表明Ponicidin通过KEAP1/NRF2促进铁凋亡，从而增强lenvatinib耐药HCC细胞的治疗敏感性。

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.