Nature: Peroxidase mediates the sensitivity of tumors to iron death.

Iron death is an iron dependence that differs from apoptosis cell death in that it is involved in a variety of degenerative diseases and represents the targetability of certain cancers.
iron-dead susceptible cell states can be pre-existing in cells in certain genealogies and obtained during cell state transition.
, however, so far, we still don't know much about the dynamic regulation of iron death susceptible.
, researchers recently published a paper in the journal Nature, using genome-wide CRISPR-Cas9 inhibitors, and found that oxidizing cytoserter peroxidases are key contributors to iron death sensitivity in human kidney and ovarian cancer cells.
In this study, to determine the factors that regulate iron death susceptivity, the researchers screened two separate genome-wide CRISPR-Cas9 inhibitors in the iron death susceptible transparent cell renal cell carcinoma (ccRCC) model 786-O3 and the high-grade serum ovarian cancer model OVCAR-8.
in both models, iron death was induced by using ML210 or 1S, 3R-RSL3 (RSL3) to inhibit lipid peroxidation repair enzyme glutathione peroxidase 4 (GPX4).
the two screenings revealed known iron death regulators - including acSL4 ), confirming the credibility of the medium used to identify iron death sensitivity.
Among previously unsealed genes that promote iron death, peroxidase components were found to be the richest cluster of genes using STRING (Protein Network Database) and a path analysis algorithm developed by researchers called Gene List Network Rich Analysis (GeLiNEA).
The peroxygene genes identified in these two screenings include the peroxidase biogene genes PEX10 and PEX3, as well as the alkyl glyceride phosphate synthase (AGPS) and fatty-coA reductase 1 (FAR1) that encode enzymes in peroxidase bodies.
other rich peroxidase genes include Glyphosate O-Acetyl Transferase (GNPAT), PEX12, and PEX7.
because peroxidases were not previously involved in iron death, the researchers focused on clarifying their possible role in the process.
using lipid group analysis, the researchers showed that peroxidases are induced by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs) as a base for lipid peroxidation, which in turn leads to iron death.
cancer cells that were initially sensitive to iron death switched to iron death resistance in mice, which was associated with a widespread reduction in PUFA-ePLs.
further discovered that the iron-promoting effects of PUFA-ePLs can be extended from tumor cells to other cell types, including neurons and myocardial cells.
In summary, this work reveals the role of peroxidase-ether-phospholipid axis in driving iron death susceptibility and avoiding iron death, highlights THEA-ePL as a unique functional lipid category, is dynamically regulated during cell state transition, and presents multiple regulatory nodes for therapeutic intervention in diseases involving iron death.
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