PCSK9 Promotes Atherosclerotic Plaque Instability by Inducing VSMC Ferroptosis through the YAP1–NUPR1 Axis

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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Publication Details

Journal
Research
Published
2025-01-01
DOI
https://doi.org/10.34133/research.0922
Citations
3
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
2.42
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article

PCSK9 Promotes Atherosclerotic Plaque Instability by Inducing VSMC Ferroptosis through the YAP1–NUPR1 Axis

Weizheng Zhang, Hengjuan Li, Ni Gan, X Wang et al.
3 citations
Research
RNA modifications and cancer
2.42
article

PCSK9 Promotes Atherosclerotic Plaque Instability by Inducing VSMC Ferroptosis through the YAP1–NUPR1 Axis

Weizheng Zhang, Hengjuan Li, Ni Gan, X Wang, Xi‐Long Zheng, Zhihan Tang, Gang Fan, Jing Yang, Xiaoyan Dai, Yanyu Chen, Mengdie Xia, Yating Zhou, Qiong Xiang, Huayu Zhang, Yuting Cui, Juan Peng, Man Li
article en
3 citations

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.

ResearchVol. 8
Sun Yat-sen University (CN), University of Calgary (CA), Hunan Normal University (CN), Shenzhen Sixth People's Hospital (CN), Second People Hospital of Hunan (CN), First Affiliated Hospital of University of South China (CN), Hunan Provincial Maternal and Child Health Hospital (CN), University of South China (CN)
Openalex Percentile: Top 10%
RNA modifications and cancer
2.42
DOIOpen Access PDFOpenAlex
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