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

Xuhui Bao; Yongjun Liang; Hanman Chang; Tianji Cai; Baijie Feng; Konstantin Gordon; Yuekun Zhu; Hailian Shi; Yundong He; Liyi Xie

doi:10.1038/s41392-023-01690-3

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

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

Authors

Xuhui Bao^{1

2

3

4

5

6}, Yongjun Liang⁷, Hanman Chang⁸, Tianji Cai⁹, Baijie Feng¹⁰, Konstantin Gordon^{11

12}, Yuekun Zhu¹³, Hailian Shi¹⁴, Yundong He¹⁵, Liyi Xie^{16

17}

Affiliations

¹ Institute of Therapeutic Cancer Vaccines, Fudan University Pudong Medical Center, Shanghai, China. xuhui_bao@fudan.edu.cn.
² Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China. xuhui_bao@fudan.edu.cn.
³ Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China. xuhui_bao@fudan.edu.cn.
⁴ Center for Clinical Research, Fudan University Pudong Medical Center, Shanghai, China. xuhui_bao@fudan.edu.cn.
⁵ Clinical Research Center for Cell-based Immunotherapy, Fudan University, Shanghai, China. xuhui_bao@fudan.edu.cn.
⁶ Department of Pathology, Duke University Medical Center, Durham, NC, USA. xuhui_bao@fudan.edu.cn.
⁷ Center for Medical Research and Innovation, Fudan University Pudong Medical Center, Shanghai, China.
⁸ Institute for Food Safety and Health, Illinois Institute of Technology, Chicago, IL, USA.
⁹ Department of Sociology, University of Macau, Taipa, Macau, China.
¹⁰ Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China.
¹¹ Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia.
¹² A. Tsyb Medical Radiological Research Center, Obninsk, Russia.
¹³ Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
¹⁴ Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai, China.
¹⁵ Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China. ydhe@bio.ecnu.edu.cn.
¹⁶ Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. xiely0922@gmail.com.
¹⁷ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. xiely0922@gmail.com.

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.

Publication types

Review

MeSH terms

Antibodies, Monoclonal / therapeutic use
Cardiovascular Diseases* / drug therapy
Cardiovascular Diseases* / genetics
Humans
Hypercholesterolemia*
Proprotein Convertase 9 / genetics
Subtilisins

Substances

PCSK9 protein, human
Proprotein Convertase 9
Antibodies, Monoclonal
Subtilisins

Abstract

Publication types

MeSH terms

Substances

Grants and funding