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靶向前蛋白转化酶枯草溶菌素 9（PCSK9）：从实验室到临床。

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.

机构信息

Institute of Therapeutic Cancer Vaccines, Fudan University Pudong Medical Center, Shanghai, China.

Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.

出版信息

Signal Transduct Target Ther. 2024 Jan 8;9(1):13. doi: 10.1038/s41392-023-01690-3.

DOI:10.1038/s41392-023-01690-3
PMID:38185721
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10772138/
Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

摘要

前蛋白转化酶枯草溶菌素 9（PCSK9）已成为脂质代谢中的关键酶，也是治疗高胆固醇血症及其相关心血管疾病（CVD）的革命性靶点。本综述详细阐述了 PCSK9 的复杂作用和广泛影响，不仅限于 CVD，还强调了其在多种生理和病理状态下的重要性，包括肝脏疾病、传染病、自身免疫性疾病，尤其是癌症。我们的研究深入探讨了 PCSK9 与低密度脂蛋白受体（LDLR）的相互作用，阐明了其对胆固醇稳态和心血管健康的重大影响。本综述还详细介绍了针对 PCSK9 的靶向治疗的发展，将基础研究发现转化为优化患者治疗的床边应用。新型 PCSK9 抑制疗法（PCSK9-iT）的出现和临床批准，包括三种单克隆抗体（依洛尤单抗、阿利西尤单抗和替伏西单抗）和一种小干扰 RNA（siRNA，inclisiran），标志着心血管医学的重大突破。这些疗法在降低胆固醇、降低心血管风险方面显示出了无与伦比的疗效，并在临床应用中展现出了巨大的价值，为心血管疾病的个体化治疗提供了新的治疗途径和充满希望的未来。此外，包括我们的研究在内的新研究揭示了 PCSK9 作为癌症预后的关键指标的潜力及其作为癌症治疗的变革性靶点的潜在应用。本综述还强调了 PCSK9 在各种癌症形式中的异常表达、与癌症预后的关联，以及其在癌症发生和癌症免疫中的关键作用。总之，本综述综合了现有知识和对 PCSK9 的新见解，全面阐述了其在重塑各种疾病治疗模式方面的变革性影响。本综述强调了 PCSK9-iT 的临床价值和效果，突出了其在推进生物医学研究领域的潜力及其在开启个体化医学新时代方面的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/a770c39331a0/41392_2023_1690_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/2cbe9b6953dc/41392_2023_1690_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/e61ede5abfb5/41392_2023_1690_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/4dc238cd86fe/41392_2023_1690_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/f21eb0af1ca3/41392_2023_1690_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/a770c39331a0/41392_2023_1690_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/2cbe9b6953dc/41392_2023_1690_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/e61ede5abfb5/41392_2023_1690_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/4dc238cd86fe/41392_2023_1690_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/f21eb0af1ca3/41392_2023_1690_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56b3/10772138/a770c39331a0/41392_2023_1690_Fig5_HTML.jpg

相似文献

[1]
Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.

Signal Transduct Target Ther. 2024-1-8

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
A Novel Small-Molecule GRP94 Modulator Increases PCSK9 Secretion and Promotes LDLR Degradation.

Life (Basel). 2025-8-20

[2]
Genetic Risk Profiles for Atherosclerosis and Venous Thromboembolism in Azorean and Mainland Portuguese Populations: A Comparative Analysis.

Curr Issues Mol Biol. 2025-8-6

[3]
HIIT and MICT mitigate endothelial dysfunction in early atherosclerotic mice via PCSK9 inhibition.

Sci Rep. 2025-8-19

[4]
Engineering chimeric PCSK9 for a vaccine against atherosclerosis.

Mol Ther Methods Clin Dev. 2025-7-12

[5]
PCSK9 Inhibitors: A Potential Priority Choice for Lipid Management in Patients with Diabetic Kidney Disease.

Drugs. 2025-8-14

[6]
Regulatory mechanisms of hepatocyte PCSK9 expression: translating mechanistic insights into potential nutraceuticals.

Chin Med. 2025-8-5

[7]
Disruption of cell-intrinsic PCSK9 enhances the antitumor efficacy of CD8 T cells.

J Immunother Cancer. 2025-7-15

[8]
Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance.

Nat Genet. 2025-6-12

[9]
Glucocorticoid treatment in early rheumatoid arthritis is independently associated with increased PCSK9 levels: data from a randomised controlled trial.

RMD Open. 2025-6-5

[10]
Chitosan-Based Nanoparticles Targeted Delivery System: In Treatment Approach for Dyslipidemia.

Int J Nanomedicine. 2025-5-24

本文引用的文献

[1]
Efficacy and safety of inclisiran a newly approved FDA drug: a systematic review and pooled analysis of available clinical studies.

Am Heart J Plus. 2022-4-2

[2]
Tafolecimab: First Approval.

Drugs. 2023-11

[3]
Tafolecimab in Chinese patients with non-familial hypercholesterolemia (CREDIT-1): a 48-week randomized, double-blind, placebo-controlled phase 3 trial.

Lancet Reg Health West Pac. 2023-9-28

[4]
Tafolecimab in Chinese Patients With Hypercholesterolemia (CREDIT-4): A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial.

JACC Asia. 2023-7-11

[5]
Natural Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Review.

Comb Chem High Throughput Screen. 2023

[6]
Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer.

iScience. 2023-5-19

[7]
PCSK9 attenuates efferocytosis in endothelial cells and promotes vascular aging.

Theranostics. 2023

[8]
Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection.

Circulation. 2023-7-25

[9]
Construction of an endoplasmic reticulum stress-related signature in lung adenocarcinoma by comprehensive bioinformatics analysis.

BMC Pulm Med. 2023-5-15

[10]
PCSK9 Inhibition in Patients After Heart Transplantation: a Retrospective Review and Literature Analysis.

Curr Heart Fail Rep. 2023-6

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