Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.
Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, China.
Mol Med. 2024 Nov 21;30(1):224. doi: 10.1186/s10020-024-01002-7.
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.
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.
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.
The present analyses indicate that hyperoside can target the NRF2/SLC7A11/GPX4 axis to induce ferroptotic CML cell death.
金丝桃苷（槲皮素-3-O-β-D-半乳糖苷）是一种从金丝桃属和山楂属植物中提取的类黄酮糖苷化合物，据报道具有多种抗炎、抗氧化和抗肿瘤特性，因此被用于治疗各种疾病。然而，它是否可以作为慢性髓性白血病（CML）细胞的有效治疗方法尚待确定。本研究旨在评估金丝桃苷对 CML 细胞的治疗作用，并阐明其作用机制。
通过 CCK-8、EDU、transwell 和流式细胞术分别分析细胞活力、增殖活性、迁移和凋亡死亡。RNA-seq 和生物信息学方法进一步评估金丝桃苷影响 CML 细胞的机制，同时用商业试剂盒检测活性氧（ROS）和游离铁的分析。透射电子显微镜用于评估线粒体形态。分子对接、细胞热转移分析（CETSA）和药物亲和反应靶标稳定性（DARTS）方法也用于探索金丝桃苷靶向 NRF2 的能力。
从机制上讲，金丝桃苷能够以被铁死亡抑制剂 ferrostatin-1 阻断的方式抑制 SLC7A11/GPX4 信号。NRF2 也与金丝桃苷介导的 SLC7A11/GPX4 轴失活密切相关，过表达 NRF2 消除了金丝桃苷治疗的益处。
本分析表明，金丝桃苷可以靶向 NRF2/SLC7A11/GPX4 轴诱导铁死亡 CML 细胞死亡。
