Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway

Yang Liu; Libo He; Binghua Liu; Yuling Ying; Junling Xu; Meng Yu; Jinye Dang; Ke Liu

doi:10.1016/j.isci.2022.104533

Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway

iScience. 2022 Jun 6;25(7):104533. doi: 10.1016/j.isci.2022.104533. eCollection 2022 Jul 15.

Authors

Yang Liu¹, Libo He¹, Binghua Liu², Yuling Ying¹, Junling Xu¹, Meng Yu¹, Jinye Dang¹, Ke Liu¹

Affiliations

¹ Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065 Sichuan, P.R.China.
² Laboratory of Molecular Biology, College of Medicine, Chengdu University, Chengdu 610106 Sichuan, P. R. China.

Abstract

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.

Keywords: Biological sciences; Cell biology; Cellular neuroscience; Neuroscience.