PCSK9 Promotes Atherosclerotic Plaque Instability by Inducing VSMC Ferroptosis through the YAP1–NUPR1 Axis
Why this work is in the frame
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Bibliographic record
Abstract
Atherosclerosis persists as a principal driver of global cardiovascular mortality and morbidity, and its sustained prevalence surge fuels the incidence of major adverse cardiovascular events (MACE). Plaque instability is a critical determinant of MACE, as fissure formation or rupture of vulnerable plaques can precipitate thromboembolic complications. In this study, we investigate a noncanonical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) beyond its lipid regulatory function, focusing on its impact on vascular smooth muscle cells (VSMCs) in the context of plaque instability. Our results demonstrate that PCSK9 overactivity markedly promotes ferroptotic cell death in VSMCs, thereby exacerbating plaque vulnerability. Furthermore, we delineate the underlying mechanism: PCSK9 physically interacts with Yes-associated protein 1 and targets it for lysosomal degradation, which, in turn, suppresses the expression of nuclear protein 1. In conclusion, our findings unveil a novel role of PCSK9 in promoting plaque instability by driving ferroptosis in VSMCs, suggesting that targeting PCSK9 presents a potential avenue for plaque stabilization, thereby mitigating the incidence of major MACE.
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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 | 0.001 | 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