Thrombin Induces ACSL4-dependent Ferroptosis During Cerebral Ischemia/reperfusion

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2022 Feb 24

PMID 35197442

Authors

Qing-Zhang Tuo

Yu Liu

Zheng Xiang

Hong-Fa Yan

Ting Zou

Yang Shu

Xu-Long Ding

Jin-Jun Zou

Shuo Xu

Fei Tang

Yan-Qiu Gong

Xiao-Lan Li

Yu-Jie Guo

Zhao-Yue Zheng

Ai-Ping Deng

Zhang-Zhong Yang

Wen-Jing Li

Shu-Ting Zhang

Scott Ayton

Ashley I Bush

Heng Xu

Lunzhi Dai

Biao Dong

Peng Lei

Affiliations

Soon will be listed here.

Abstract

Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes/proteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.

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