Identification of KW-2449 as a dual inhibitor of ferroptosis and necroptosis reveals that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Yaxing Zhao, Qingsong Wang, Jing Zhu, Jin Cai, Xiaona Feng, Qianqian Song, Hui Jiang, Wenqing Ren, Yuan He, Ping Wang, Du Feng, Jianqiang Yu, Yue Liu, Qihui Wu, Jitkaew Siriporn, Zhenyu Cai
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Abstract

Necroptosis and ferroptosis are two distinct forms of necrotic-like cell death in terms of their morphological features and regulatory mechanisms. These two types of cell death can coexist in disease and contribute to pathological processes. Inhibition of both necroptosis and ferroptosis has been shown to enhance therapeutic effects in treating complex necrosis-related diseases. However, targeting both necroptosis and ferroptosis by a single compound can be challenging, as these two forms of cell death involve distinct molecular pathways. In this study, we discovered that KW-2449, a previously described necroptosis inhibitor, also prevented ferroptosis both in vitro and in vivo. Mechanistically, KW-2449 inhibited ferroptosis by targeting the autophagy pathway. We further identified that KW-2449 functioned as a ULK1 (Unc-51-like kinase 1) inhibitor to block ULK1 kinase activity in autophagy. Remarkably, we found that Necrostatin-1, a classic necroptosis inhibitor that has been shown to prevent ferroptosis, also targets the autophagy pathway to suppress ferroptosis. This study provides the first understanding of how necroptosis inhibitors can prevent ferroptosis and suggests that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis. Therefore, the identification and design of pharmaceutical molecules that target the autophagy pathway from necroptosis inhibitors is a promising strategy to develop dual inhibitors of necroptosis and ferroptosis in clinical application.

KW-2449是铁突变和坏死的双重抑制剂,它揭示了自噬是坏死抑制剂防止铁突变的目标途径。
坏死和铁死是两种形态特征和调控机制截然不同的坏死样细胞死亡形式。这两种细胞死亡可在疾病中并存,并对病理过程起作用。研究表明,抑制坏死凋亡和铁凋亡可增强治疗复杂坏死相关疾病的疗效。然而,用一种化合物同时靶向坏死和铁凋亡可能具有挑战性,因为这两种细胞死亡形式涉及不同的分子途径。在这项研究中,我们发现 KW-2449(一种先前描述过的坏死抑制剂)也能在体外和体内阻止铁凋亡。从机理上讲,KW-2449 是通过靶向自噬途径来抑制铁凋亡的。我们进一步发现,KW-2449可作为ULK1(Unc-51-like kinase 1,类ULK1激酶1)抑制剂,阻断ULK1激酶在自噬过程中的活性。值得注意的是,我们发现 Necrostatin-1 这种典型的坏死抑制剂也能靶向自噬途径来抑制铁突变。这项研究首次揭示了坏死抑制剂是如何阻止铁锈蚀的,并表明自噬是坏死抑制剂阻止铁锈蚀的一个靶向途径。因此,从坏死蛋白抑制剂中鉴定和设计出靶向自噬途径的药物分子,是开发坏死蛋白和铁蛋白沉积双重抑制剂在临床应用中的一种很有前景的策略。
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
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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