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

Signal Transduction and Targeted Therapy 2024年第2期9卷 509-557页

作者： Xuhui Bao Yongjun Liang hanman chang Tianji Cai Baijie Feng Konstantin Gordon Yuekun Zhu Hailian Shi Yundong He Liyi Xie Institute of Therapeutic Cancer Vaccines Fudan University Pudong Medical CenterShanghaiChina Shanghai Key Laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghaiChina Department of Oncology Fudan University Pudong Medical CenterShanghaiChina Center for Clinical Research Fudan University Pudong Medical CenterShanghaiChina Clinical Research Center for Cell-based Immunotherapy Fudan UniversityShanghaiChina Department of Pathology Duke University Medical CenterDurhamNCUSA Center for Medical Research and Innovation Fudan University Pudong Medical CenterShanghaiChina Institute for Food Safety and Health Illinois Institute of TechnologyChicagoILUSA Department of Sociology University of MacaoTaipaMacaoChina Medical Institute Peoples’Friendship University of RussiaMoscowRussia A.Tsyb Medical Radiological Research Center ObninskRussia Department of Colorectal Surgery The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineZhangjiang Hi-tech ParkShanghaiChina Department of Radiation Oncology Fudan University Shanghai Cancer CenterShanghaiChina Department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina

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

关键词： PCSK9 metabolism convert

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