CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes.
CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes.
复制标题
CGI1746靶向σ1R，通过线粒体相关膜调控铁死亡。
DOI：
10.1038/s41589-023-01512-1
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发表时间：
2024-01
影响因子：
14.8
通讯作者：
Zili Zhang;Hong Zhou;Wenjia Gu;Yuehan Wei;Shan Mou;Youjun Wang;Jing Zhang;Qing Zhong
中科院分区：
文献类型：
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作者：
Zili Zhang;Hong Zhou;Wenjia Gu;Yuehan Wei;Shan Mou;Youjun Wang;Jing Zhang;Qing Zhong
铁凋亡是铁依赖性氧化性细胞死亡。不稳定铁和含多不饱和脂肪酸（PUFA）的脂质是铁凋亡的两个关键因素。许多调节铁稳态和脂质合成的过程在铁凋亡中起关键作用。然而，目前还不清楚是否生物过程以外的铁稳态和脂质合成与铁凋亡。使用激酶抑制剂文库筛选，我们发现了一种名为CGI 1746的小分子，其有效地阻断铁凋亡。进一步的研究表明，CGI 1746通过σ-1受体（σ 1 R）（一种主要位于细胞相关膜（MAMs）的伴侣蛋白）抑制铁凋亡。抑制σ 1 R可保护小鼠免受顺铂诱导的急性肾损伤，其特征为铁凋亡。从机制上讲，CGI 1746处理或MAMs的遗传破坏导致Ca 2+转移缺陷、线粒体活性氧（ROS）产生和含PUFA的三酰甘油积累。因此，我们提出了一个关键的作用，MAMs在ferroptosis执行。
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. Suppression of σ1R protects mice from cisplatin-induced acute kidney injury hallmarked by ferroptosis. Mechanistically, CGI1746 treatment or genetic disruption of MAMs leads to defective Ca2+transfer, mitochondrial reactive oxygen species (ROS) production and PUFA-containing triacylglycerol accumulation. Therefore, we propose a critical role for MAMs in ferroptosis execution.