Plasticity of ether lipids promotes ferroptosis susceptibility and evasion
By Y. Zou, Whitney S. Henry, E. Ricq, E. T. Graham, Vaishnavi V. Phadnis, Pema Maretich, Sateja Paradkar, Natalie Boehnke, A. Deik, Ferenc Reinhardt and 12 more. Nature, 2020
728 citations recorded by the source corpus.
Ferroptosis—an iron-dependent, non-apoptotic cell death process—is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2–5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR–Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome–ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis. The cellular organelles peroxisomes contribute to the sensitivity of cells to ferroptosis by synthesizing polyunsaturated ether phospholipids, and changes in the abundances of these lipids are associated with altered sensitivity to ferroptosis during cell-state transitions.
Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/b19f10bb159798ef64f7a2d9c5151b95b30f03aa
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cancer Research
In Molecular Biology
In Pulmonary and Respiratory Medicine
Citations in the corpus
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, methodology): “52,70 On the contrary, phospholipase A2 group VI (iPLA2 β ) cleaves oxidized PUFA tails from PLs to suppress p53-driven ferroptosis.”
- Ferroptosis: mechanisms and links with diseases (2021, background): “In a further study of the ferroptosis sensitivity gene via genome-wide CRISPR–Cas9 suppressor screens, oxidative organelles peroxisomes were found to help the cancer cells escape and increase the susceptibility to ferroptosis through synthesizing polyunsaturated ether phospholipids (PUFA-ePL).(24)”
- The cell biology of ferroptosis (2024, neutral): “Genetic disruption of peroxisome biogenesis or peroxisomal AGP synthesis suppresses ferroptosis in renal cell carcinoma models, hepatocellular carcinoma models and endometrial carcinoma models, concomitant with a reduction in the levels of PUFA-containing ether lipid species 25 .”
- Ferroptosis in infection, inflammation, and immunity (2021, background): “In addition to free PUFAs, i.e., the polyunsaturated ether phospholipids (PUFA-ePLs) synthesized in peroxisome (Zou et al., 2020a), lysosomal degradation of lipid droplets by lipophagy (Bai et al., 2019) or glutamine-derived anaplerotic flux that provides α-ketoglutarate to the tricarboxylic acid…”