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CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes

Nature Chemical Biology. 2024-01; 
Zili Zhang, Hong Zhou, Wenjia Gu, Yuehan Wei, Shan Mou, Youjun Wang, Jing Zhang & Qing Zhong
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摘要

Ferroptosis is iron-dependent oxidative cell death. Labile iron and polyunsaturated fatty acid (PUFA)-containing lipids are two critical factors for ferroptosis execution. Many processes regulating iron homeostasis and lipid synthesis are critically involved in ferroptosis. However, it remains unclear whether biological processes other than iron homeostasis and lipid synthesis are associated with ferroptosis. Using kinase inhibitor library screening, we discovered a small molecule named CGI1746 that potently blocks ferroptosis. Further studies demonstrate that CGI1746 acts through sigma-1 receptor (σ1R), a chaperone primarily located at mitochondria-associated membranes (MAMs), to inhibit ferroptosis. Suppress... More

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