福莫西汀通过靶向 NADPH 氧化酶 4 在活化的肝星状细胞中诱导铁变态反应以减轻肝纤维化

IF 6.1 2区 医学 Q1 CHEMISTRY, MEDICINAL Phytotherapy Research Pub Date : 2024-10-30 DOI:10.1002/ptr.8338
Ming-Xuan Liu, Ying-Ying Gu, Wen-Yuan Nie, Xiao-Ming Zhu, Meng-Jing Qi, Rui-Min Zhao, Wei-Zhong Zhu, Xiao-Ling Zhang
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引用次数: 0

摘要

铁突变是一种新发现的细胞死亡类型,在肝纤维化中发挥着至关重要的作用。福莫西汀(FMN)是一种天然异黄酮化合物,主要从邓氏刺五加(Spatholobus suberectus Dunn)中分离出来,具有抗氧化、抗炎和保肝等多种生物活性。本研究旨在探索 FMN 在肝纤维化中的调控机制,以及 NADPH 氧化酶 4(NOX4)与铁氧化的关系。研究人员在大鼠CCl4诱导的肝纤维化模型中评估了FMN对造血干细胞铁突变的影响。在体外,用N-乙酰-L-半胱氨酸(NAC)和去氧胺(DFO)阻断铁氧化,然后探讨FMN的抗纤维化作用。通过生物正交点击化学反应以及药物亲和力反应靶标稳定性(DARTS)、细胞热转移(CETSA)、表面等离子体共振(SPR)检测和等温滴定量热法(ITC)分析,确定了FMN的靶蛋白。在这里,我们发现 FMN 通过诱导活化造血干细胞中的铁突变发挥抗纤维化作用。NAC 和 DFO 阻止了 FMN 诱导的铁析出细胞死亡和胶原减少。此外,FMN 通过可能的活性氨基酸残基位点直接与 NOX4 结合,提高了以 NOX4 为基础的 NADPH 氧化酶的活性,从而提高了 NADP+/NADPH 的水平,促进了活化造血干细胞的铁蜕变,缓解了肝纤维化。这些结果表明了 FMN 改善肝纤维化的直接靶点和机制,表明 FMN 可能是进一步开发肝纤维化疗法的天然候选药物。
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Formononetin Induces Ferroptosis in Activated Hepatic Stellate Cells to Attenuate Liver Fibrosis by Targeting NADPH Oxidase 4.

Ferroptosis is a newly discovered type of cell death that exerts a crucial role in hepatic fibrosis. Formononetin (FMN), a natural isoflavone compound mainly isolated from Spatholobus suberectus Dunn, shows multiple biological activities, including antioxidant, anti-inflammatory, and hepatoprotection. This research aims to explore the regulatory mechanism of FMN in liver fibrosis and the relationship between NADPH oxidase 4 (NOX4) and ferroptosis. The effects of FMN on HSC ferroptosis were evaluated in rat model of CCl4-induced hepatic fibrosis. In vitro, N-acetyl-L-cysteine (NAC) and deferoxamine (DFO) were used to block ferroptosis and then explored the anti-fibrotic effect of FMN. The target protein of FMN was identified by bio-orthogonal click chemistry reaction as well as drug affinity responsive target stability (DARTS), cellular thermal shift (CETSA), surface plasmon resonance (SPR) assays, and isothermal titration calorimetry (ITC) analysis. Here, we found that FMN exerted anti-fibrotic effects via inducing ferroptosis in activated HSCs. NAC and DFO prevented FMN-induced ferroptotic cell death and collagen reduction. Furthermore, FMN bound directly to NOX4 through possible active amino acid residues sites, and increased NOX4-based NADPH oxidase activity to enhance levels of NADP+/NADPH, thus promoting ferroptosis of activated HSCs and relieving liver fibrosis. These results demonstrate that the direct target and mechanism by which FMN improves liver fibrosis, suggesting that FMN may be a natural candidate for further development of liver fibrosis therapy.

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来源期刊
Phytotherapy Research
Phytotherapy Research 医学-药学
CiteScore
12.80
自引率
5.60%
发文量
325
审稿时长
2.6 months
期刊介绍: Phytotherapy Research is an internationally recognized pharmacological journal that serves as a trailblazing resource for biochemists, pharmacologists, and toxicologists. We strive to disseminate groundbreaking research on medicinal plants, pushing the boundaries of knowledge and understanding in this field. Our primary focus areas encompass pharmacology, toxicology, and the clinical applications of herbs and natural products in medicine. We actively encourage submissions on the effects of commonly consumed food ingredients and standardized plant extracts. We welcome a range of contributions including original research papers, review articles, and letters. By providing a platform for the latest developments and discoveries in phytotherapy, we aim to support the advancement of scientific knowledge and contribute to the improvement of modern medicine.
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