Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Abstract

Ferroptosis, an iron-dependent, non-apoptotic cell death program, is involved in various degenerative diseases and represents a targetable vulnerability in certain cancers 1 . The ferroptosissusceptible cell state can either preexist in cells arising from certain lineages or be acquired during cell-state transitions 2-5 . Precisely how ferroptosis susceptibility is dynamically regulated remains poorly understood. Using genome-wide CRISPR/Cas9 suppressor screens, we identify the peroxisome organelle as a critical contributor to ferroptosis sensitivity in human renal and ovarian carcinoma cells. By lipidomic profiling, we show that peroxisomes contribute to ferroptosis through the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), an understudied lipid *

The diversity and breadth of cancer cell fatty acid metabolism

“…Further, this altered MUFA/PUFA ratio is advantageous for cancer cells as it results in fewer peroxidation susceptible targets and reduced susceptibility to ferroptosis (i.e., iron-dependent cell death) [191]. Recent studies have provided new insights into the mechanisms that regulate ferroptosis, including the requirement for acyl-CoA synthetase activity [191,192] and the enrichment of PUFA in ether phospholipids [193] and PEs [194]. These studies and others (see review [195]) provide advances in our understanding of the mechanisms that regulate ferroptosis; however, the precise role that PUFA synthesis, that is catalyzed by delta-6 and delta-5 desaturases, in ferroptosis activation and cell death in cancer remains to be defined.…”

Identification of Circulating Endocan-1 and Ether Phospholipids as Biomarkers for Complications in Thalassemia Patients

“…Their lower level in thalassemia patients could therefore be linked to pathological mechanisms, namely high oxidative stress or inflammatory status [49,50], and/or reflect a prevailing mitochondrial/peroxisomal dysfunction in one or more organs. An intriguing emerging theme of research is the significance of ferroptosis in cardiometabolic diseases, particularly relevant to this study since a recent paper found that low levels of ether lipids PUFAs may protect against cell susceptibility to ferroptosis [51]. Of particular interest in our current study, most of the circulating ether PC or PE were significantly and differentially associated with specific clinical parameters, both blood and heart parameters, emphasizing their relevance to the status of TDT patients.…”

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

“…Subsequently, we investigated the regulation of the different lipids by their fold change, and found that both anthracyclins increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethanolamines (etherPEs) with PUFAs in all cell lines (Scheme 1). In the light of previous research, these lipids are involved in programmed cell death by ferroptosis 18 . The changes in cholesterol lipids were cell-type specific, as they increased in Huh7 and SNU449 cells, but did not present a clear trend in HepG2.…”

“…We also present evidence that the regulation of cholesterol lipids and de novo lipogenesis by anthracyclins is cell-type dependent for three different cell lines of primary liver cancer. As etherPEs with PUFAs are involved in programmed cell death by ferroptosis 18 and statins have been suggested as anthracyclin adjuvants 29 , this metabolic characterization may help to design general and personalized metabochemotherapies for improved cancer treatments.…”

“…Second, we found a general increase of etherPEs with PUFAs. It is known that: i) glycerophospholipids of ethanolamine with PUFAs are necessary for ferroptosis 57 ; and ii) etherGLs with PUFAs present a critical contribution to ferroptosis 18 . It is plausible that the increase of etherPEs with PUFAs can be considered a hallmark of ferroptosis in primary liver cancer treated with anthracyclins.…”