Hyperoside induces ferroptosis in chronic myeloid leukemia cells by targeting NRF2.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Medicine Pub Date : 2024-11-21 DOI:10.1186/s10020-024-01002-7

Junyi Wei, Quanyou Chai, Yuqiao Qin, Long Li, Chunling Guo, Zhaoyang Lu, Huimin Liu

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引用次数: 0

Abstract

Background: Hyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside compound derived from plants in the Hypericum and Crataegus genera that reportedly exhibits an array of anti-inflammatory, antioxidant, and antitumor properties such that it has been used to treat various diseases. Whether it can serve as an effective treatment for chronic myeloid leukemia (CML) cells, however, has yet to be established. The present study was thus devised to assess the therapeutic effects of hyperoside on CML cells and to clarify the underlying mechanism of action.

Methods: Cellular viability, proliferative activity, migration, and apoptotic death were respectively analyzed through CCK-8, EDU, transwell, and flow cytometry assays. RNA-seq and bioinformatics approaches were further employed to evaluate the mechanisms through which hyperoside influences CML cells, while analyses of reactive oxygen species (ROS) and free iron were detected with commercial kits. Transmission electron microscopy was used to assess mitochondrial morphology. Molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) approaches were also used to explore the ability of hyperoside to target NRF2.

Results: From a mechanistic perspective, hyperoside was able to inhibit SLC7A11/GPX4 signaling in a manner that was abrogated by the ferroptosis inhibitor ferrostatin-1. NRF2 was also closely associated with the inactivation of the SLC7A11/GPX4 axis mediated by hyperoside such that overexpressing NRF2 ablated the benefits associated with hyperoside treatment.

Conclusions: The present analyses indicate that hyperoside can target the NRF2/SLC7A11/GPX4 axis to induce ferroptotic CML cell death.

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金丝桃苷通过靶向 NRF2 诱导慢性髓性白血病细胞的铁变态反应

背景：金丝桃苷（槲皮素-3-O-β-D-吡喃半乳糖苷）是从金丝桃属和山楂属植物中提取的一种黄酮醇苷化合物，据报道具有一系列抗炎、抗氧化和抗肿瘤特性，因此已被用于治疗多种疾病。然而，它是否能有效治疗慢性髓性白血病（CML）细胞尚待证实。因此，本研究旨在评估金丝桃苷对 CML 细胞的治疗效果，并阐明其潜在的作用机制：方法：分别通过CCK-8、EDU、跨孔和流式细胞术分析细胞活力、增殖活性、迁移和凋亡。进一步采用 RNA-seq 和生物信息学方法来评估金丝桃苷影响 CML 细胞的机制，同时使用商业试剂盒检测活性氧（ROS）和游离铁。透射电子显微镜用于评估线粒体形态。分子对接、细胞热转移试验（CETSA）和药物亲和力反应靶点稳定性（DARTS）方法也被用来探索金丝桃苷靶向NRF2的能力：结果：从机理的角度来看，金丝桃苷能够抑制SLC7A11/GPX4信号传导，而铁蛋白沉积抑制剂铁司他丁-1则会减弱这种抑制作用。NRF2也与金丝桃苷介导的SLC7A11/GPX4轴的失活密切相关，因此过表达NRF2会消减金丝桃苷治疗带来的益处：结论：目前的分析表明，金丝桃苷可以靶向 NRF2/SLC7A11/GPX4 轴，诱导铁性 CML 细胞死亡。

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

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.