Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway.
Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway.
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鞘脂合成的药理学抑制通过刺激 HIF-1 途径减少铁死亡
DOI：
10.1016/j.isci.2022.104533
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发表时间：
2022-07-15
期刊：
影响因子：
5.8
通讯作者：
Liu, Ke
中科院分区：
文献类型：
--
作者：
Liu, Yang;He, Libo;Liu, Binghua;Ying, Yuling;Xu, Junling;Yu, Meng;Dang, Jinye;Liu, Ke
铁下垂在许多神经系统疾病的病理中起着至关重要的作用。在这里，我们发现用肉豆杉素（一种神经鞘脂从头合成的抑制剂）预处理可以显著降低erastin或谷氨酸诱导的HT22细胞铁凋亡，而不需要细胞内谷胱甘肽的恢复。对HT22细胞进行转录组分析，发现缺氧诱导因子1 （HIF-1）通路是一个主要的新型药物靶点。进一步的研究证实，肉豆蔻素的细胞保护作用需要HIF1α。肉豆蔻素处理促进了HIF-1通路效应物PDK1和BNIP3的表达，并改变了细胞内葡萄糖代谢产物的水平。此外，肉豆蔻素处理通过降低其泛素化和蛋白酶体降解来稳定HIF1α蛋白。在其他哺乳动物细胞系中也发现了肉豆蔻素对HIF1α稳定的类似作用，表明这是肉豆蔻素细胞保护作用的共同机制。肉豆蔻素抑制鞘脂合成减少铁下垂肉豆蔻素激活HIF-1通路肉豆蔻素对铁下垂的作用需要HIF1α肉豆蔻素通过降低HIF1α泛素化来稳定HIF1α蛋白神经科学;细胞神经科学;细胞生物学
Ferroptosis is crucial to the pathology of many neurological diseases. Here, we found pre-treatment with myriocin, an inhibitor of de novo synthesis of sphingolipid, significantly decreased the erastin- or glutamate-induced ferroptosis of HT22 cells without requiring the recovery of intracellular glutathione. The transcriptome analysis of HT22 cells treated with or without myriocin identified the hypoxia-inducible factor 1 (HIF-1) pathway as a prime and novel drug target. Further study validated that HIF1α was required for the cytoprotective effects of myriocin. Myriocin treatment promoted the expression of HIF-1 pathway effectors including PDK1 and BNIP3 and altered the intracellular levels of glucose metabolites. Additionally, myriocin treatment stabilized HIF1α protein by decreasing its ubiquitination and proteasomal degradation. Similar effects of myriocin on HIF1α stabilization were also found in other mammalian cell lines indicating this is a common mechanism for the cytoprotective role of myriocin. Inhibiting sphingolipid synthesis by myriocin reduces the ferroptosis Myriocin activates the HIF-1 pathway The effects of myriocin on ferroptosis require HIF1α Myriocin stabilizes HIF1α protein by reducing its ubiquitination Biological sciences; Neuroscience; Cellular neuroscience; Cell biology
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影响因子：
5.3
作者：
Cutler, Roy G.;Thompson, Kenneth W.;Camandola, Simonetta;Mack, Kendra T.;Mattson, Mark P.
通讯作者：
Mattson, Mark P.
影响因子：
5.6
作者：
Giussani P;Tringali C;Riboni L;Viani P;Venerando B
通讯作者：
Venerando B
影响因子：
2.9
作者：
Epsztejn, S;Kakhlon, O;Cabantchik, ZI
通讯作者：
Cabantchik, ZI
影响因子：
3
作者：
Albrecht, Philipp;Lewerenz, Jan;Methner, Axel
通讯作者：
Methner, Axel
影响因子：
4.7
作者：
Befani, Christina D.;Vlachostergios, Panagiotis J.;Liakos, Panagiotis
通讯作者：
Liakos, Panagiotis