Potent Ferroptosis Inhibitors Can Catalyze the Cross-Dismutation of Phospholipid-Derived Peroxyl Radicals and Hydroperoxyl Radicals
Bibliographic record
Abstract
Nitroxides were recently shown to catalyze the cross-dismutation of alkylperoxyl and hydroperoxyl radicals, making them uniquely effective radical-trapping antioxidants (RTAs) in unsaturated hydrocarbons where both species are formed. Given the abundance of unsaturated lipids in biological membranes, the continuous generation of hydroperoxyl (superoxide) as a byproduct of aerobic respiration, and the demonstrated cytoprotective properties of some nitroxides, we probed if cross-dismutation operates in phospholipid bilayers and cell culture. Interestingly, only nitroxides that were efficiently converted to amines in situ were effective, with their activity paralleling the stability of the incipient aminyl radicals. The ether-linked diarylamine phenoxazine, one of the most potent RTAs known, was particularly effective as a cross-dismutation catalyst. In contrast, phenolic RTAs such as α-tocopherol (α-TOH), the most potent form of vitamin E, were found to be inefficient due to the preference for the combination of hydroperoxyl and phenoxyl radicals over H-atom transfer between them. Experiments carried out in mouse embryonic fibroblasts corroborated these findings. Cells cotreated with phenoxazine (or its nitroxide) and a superoxide source were better protected from ferroptosis than those treated with phenoxazine (or its nitroxide) alone. No such synergy was observed for cells treated with α-TOH. Live cell imaging established that cytoprotection was associated with suppression of (phospho)lipid peroxidation. These results highlight the remarkable capacity for select amines to act as effective phase-transfer catalysts for a reducing equivalent (an H atom), such that a water-soluble “reactive oxygen species” can be used to quench a lipid-soluble one.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".