Abstract
It is well established that ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free radicals or enzymatic stimulation of lipoxygenase. Although there is emerging evidence that long-chain saturated fatty acid (SFA) might be implicated in ferroptosis, it remains unclear whether and how SFA participates in the process of ferroptosis. Using endogenous metabolites and genome-wide CRISPR screening, we have identified FAR1 as a critical factor for SFA-mediated ferroptosis. FAR1 catalyzes the reduction of C16 or C18 saturated fatty acid to fatty alcohol, which is required for the synthesis of alkyl-ether lipids and plasmalogens. Inactivation of FAR1 diminishes SFA-dependent ferroptosis. Furthermore, FAR1-mediated ferroptosis is dependent on peroxisome-driven ether phospholipid biosynthesis. Strikingly, TMEM189, a newly identified gene which introduces vinyl-ether double bond into alkyl-ether lipids to generate plasmalogens abrogates FAR1-alkyl-ether lipids axis induced ferroptosis. Our study reveals a new FAR1-ether lipids-TMEM189 axis dependent ferroptosis pathway and suggests TMEM189 as a promising druggable target for anticancer therapy.
Highlights
1234567890();,: 1234567890();,: Ether phospholipids represent an important group of phospholipids containing a glycerol backbone with an alkyl or a vinyl bond connecting a fatty alcohol at sn-1 position, usually polyunsaturated fatty acid (PUFA) including docosahexaenoic acid and arachidonic acid at sn-2
There is a tight correlation between glucose, lipid and amino acid metabolism, suggesting that there are alternative metabolites involved in the process of ferroptosis
The cells treated with 1-HE were sensitive to ferroptosis (Fig. 1c, Supplementary Fig. S1a). 1-HE mediated cell death was completely blocked by ferroptosis inhibitor ferrostatin-1 (Fer-1) but not by the apoptosis inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]fluoromethylketone (Z-VAD-FMK), the necroptosis inhibitor necrostatin-1 or autophagy inhibitor 3-MA (Fig. 1d, e, j, Supplementary Fig. S1b). 1-HE mediated ferroptosis can be induced by another glutathione peroxidase 4 (GPX4) inhibitor ML210, cystine starvation, erastin-suppressed cysteine uptake or TBHinduced reactive oxygen species (ROS) (Fig. 1f–i)
Summary
Recent studies have been reported the endogenous metabolites in the glucose metabolism pathway are implicated in ferroptosis besides cysteine-GSH pathway [24, 25], it is little known whether a network system of metabolites regulates ferroptosis. Analysis of the cancer dependency map (DepMap; https:// depmap.org/portal/) revealed that the expression levels of FAR1 are positively correlated with AGPS and acyl-CoA synthetase long-chain family member 4 (ACSL4) (Supplementary Fig. S4b), which incorporates free lipid acids such as PUFAs into phospholipids (PL-PUFAs) [20, 21] Taken together, these findings demonstrate the specific requirement of FAR1 for ferroptotic cell death in cancer cells. Kaplan–Meier survival analysis demonstrated that high expression of FAR1 is associated with improved overall survival in patients with other types of cancers including liver cancer, rectum adenocarcinoma and bladder carcinoma (Supplementary Fig. S4g) Taken together, these data demonstrate that FAR1 is positively correlated with ferroptosis responses in renal IRI and tumors, implying a potential role of FAR1 as a tumor suppresser via ferroptosis. These data imply that TMEM189 might facilitate tumorigenesis through ferroptosis resistance
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