YTHDF1 promotes p53 translation and induces ferroptosis during acute cerebral ischemia/reperfusion through m6A-dependent binding
Why this work is in the frame
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Bibliographic record
Abstract
Abstract The rapid escalation of oxidative and nitrosative stress during ischemia/reperfusion (I/R) triggers neuronal damage, leading to severe neurological deficits and long-term disability. N6-methyladenosine (m 6 A), a highly abundant RNA modification in the brain, undergoes dynamic changes following acute I/R injury, and regulates stroke pathogenesis and neurological outcomes. However, the molecular mechanisms by which m 6 A influences acute I/R injury responses remain elusive. Our study reveals that the expression of key I/R pathogenesis pathways positively correlates with the expression of m 6 A reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of m 6 A, results in bidirectional changes in oxidative stress response and neuronal viability under I/R conditions. We have identified p53 mRNA as a critical target of m 6 A methylation and YTHDF1, driving the translation of p53 protein in a context- and m 6 A-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the m 6 A reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I/R injury. Graphical abstract m 6 A-dependent YTHDF1 binding to p53 mRNA promotes its translation and ferroptosis during acute cerebral ischemia/reperfusion (I/R) Critical points: • I/R upregulates YTHDF1 expression and its binding to m 6 A-modfied p53 mRNA; • Binding by YTHDF1 promotes translation of p53 mRNA and induces ferroptosis; • AAV-mediated knockdown of YTHDF1 alleviates I/R-induced neuronal damage in acute phase.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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 it