Dovitinib Ameliorates Inflammation-Related Diseases by Inhibiting Necroptosis and Ferroptosis

IF 3.8 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yingying Lin, Jianting Feng, Mingyuan Zhao, Libo Zhang, Yan Li, Xuan Chen, Chuibing Lin, Junxiong Lin, Qiaofa Lin, Jingyi Li, Lanqin Wu* and Lisheng Li*, 
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引用次数: 0

Abstract

Abnormal and dysregulated cell death plays important roles in organ injury. Necroptosis and ferroptosis are two distinct types of regulated cell death that can trigger inflammation and are involved in organ injury. The inhibition of necroptosis and ferroptosis is proposed to be beneficial for treating multiple pathological conditions. To find out necroptosis and ferroptosis inhibitors, we used a small-molecule compound library for screening and identified a clinically advanced compound, Dovitinib (Dov), as a potent dual inhibitor of necroptosis and ferroptosis. Dov inhibited tumor necrosis factor (TNF)-induced necroptosis by regulating receptor-interacting protein kinase 1 (RIPK1) and alleviated TNF-mediated systemic inflammatory response syndrome. Additionally, Dov inhibited ferroptosis by regulating the NRF2/HMOX1 axis and lipid peroxidation and protected against concanavalin A-induced acute liver injury. Thus, our work revealed that Dov is a dual inhibitor of necroptosis and ferroptosis and provides a potential therapeutic drug or combination approach for treating necroptosis- and ferroptosis-related diseases.

Abstract Image

多维替尼通过抑制坏死性下垂和铁下垂改善炎症相关疾病。
细胞死亡异常和失调在器官损伤中起着重要作用。坏死性上睑下垂和铁性上睑下垂是两种不同类型的细胞死亡,可引发炎症并涉及器官损伤。对坏死性上睑下垂和铁上睑下垂的抑制被认为对治疗多种病理条件有益。为了寻找necroptosis和ferroptosis抑制剂,我们使用小分子化合物文库进行筛选,并鉴定出一种临床进展的化合物Dovitinib (Dov),作为一种有效的necroptosis和ferroptosis双重抑制剂。Dov通过调节受体相互作用蛋白激酶1 (RIPK1)抑制肿瘤坏死因子(TNF)诱导的坏死下垂,减轻TNF介导的全身炎症反应综合征。此外,Dov通过调节NRF2/HMOX1轴和脂质过氧化抑制铁下沉,并对豆豆蛋白a诱导的急性肝损伤有保护作用。因此,我们的工作揭示了Dov是坏死性上睑下垂和铁下垂的双重抑制剂,为治疗坏死性上睑下垂和铁下垂相关疾病提供了潜在的治疗药物或联合方法。
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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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