CRCardiovascular Reviews3083-48802981-8109Bio-Byword Scientific Publishing Pty. Ltd.10.26689/cr.v3i4.13473ArticleClinical Application of PCSK9 Inhibitor in Tumor Therapyhttps://artdesignp.com/journal/CR/3/4/10.26689/cr.v3i4.13473LuWenjie,ELusha2025342025-12-31Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a key protein secreted by the liver, initially emerged as a research focus in the cardiovascular field due to its central role in regulating lipid metabolism. With the deepening of research, the functional scope of PCSK9 and its inhibitors has continued to expand. They not only demonstrate remarkable efficacy in lipid management and the prevention/treatment of atherosclerotic cardiovascular disease (ASCVD) but also show enormous potential value in cancer prevention and control. Beyond indirectly regulating tumor progression by modulating lipid and inflammatory metabolism, PCSK9 may also exert direct effects on tumorigenesis and progression by participating in tumor cell proliferation, apoptosis signaling pathways, and immune regulation (e.g., influencing the expression of LDLR-related molecules on the surface of immune cells). However, no unified consensus has been reached in existing mechanistic studies. Regarding clinical evidence, there is heterogeneity among the results of multiple cohort studies and clinical trials. Some studies indicate that PCSK9 inhibitors do not significantly increase cancer risk or cancer-related mortality, and even some data suggest potential protective effects against specific types of tumors. Conversely, a small number of studies imply that long-term use may be associated with a slight elevation in the risk of certain cancers. Such discrepancies may stem from heterogeneity in sample size, follow-up duration, tumor types, and baseline characteristics of the study populations. Based on a review of numerous relevant studies, this article concludes that PCSK9 inhibitors may become a key therapeutic agent for cancer treatment in the future.

Collaboration GBODC, Kocarnik J, Compton K, et al., 2022, Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncology, 8(3): 420–444.

Mokmeli S, Tehrani G, Zamiri R, et al., 2016, Investigating the Frequency of the ERCC1 Gene C8092A Polymorphism in Iranian Patients with Advanced Gastric Cancer Receiving Platinum-based Chemotherapy. Asian Pacific Journal of Cancer Prevention: APJCP, 17(3): 1369–1372.

Ghahremanfard F, Mirmohammadkhani M, Shahnazari B, et al., 2015, The Valuable Role of Measuring Serum Lipid Profile in Cancer Progression. Oman Medical Journal, 30(5): 353–357.

Ungvari Z, Menyhart O, Lehoczki A, et al., 2025, PCSK9 Expression and Cancer Survival: A Prognostic Biomarker at the Intersection of Oncology and Geroscience. GeroScience.

Ding W, Chen L, Xia J, et al., 2024, Causal Association between Lipid-lowering Drugs and Cancers: A Drug Target Mendelian Randomization Study. Medicine, 103(18): e38010.

Xu B, Li S, Fang Y, et al., 2020, Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation. Frontiers in Oncology, 2020(10): 609663.

Ito M, Hiwasa T, Oshima Y, et al., 2021, Association of Serum Anti-PCSK9 Antibody Levels with Favorable Postoperative Prognosis in Esophageal Cancer. Frontiers in Oncology, 2021(11): 708039.

He M, Hu J, Fang T, et al., 2021, Protein Convertase Subtilisin/Kexin Type 9 Inhibits Hepatocellular Carcinoma Growth by Interacting with GSTP1 and Suppressing the JNK Signaling Pathway. Cancer Biology & Medicine, 19(1): 90–103.

Alannan M, Seidah N, Merched A, 2022, PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity. Cells, 11(24): 4132.

Jin W, Yu J, Su Y, et al., 2023, Drug Repurposing Flubendazole to Suppress Tumorigenicity via PCSK9-Dependent Inhibition and Potentiate Lenvatinib Therapy for Hepatocellular Carcinoma. International Journal of Biological Sciences, 19(7): 2270–2288.

Xu W, Hu M, Lu X, et al., 2024, Inhibition of PCSK9 Enhances the Anti-Hepatocellular Carcinoma Effects of TCR-T Cells and Anti-PD-1 Immunotherapy. International Journal of Biological Sciences, 20(10): 3942–3955.

Ioannou G, Lee S, Linsley P, et al., 2022, Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol. Hepatology Communications, 6(4): 780–794.

Guo S, Xia X, Gu H, et al., 2020, Proprotein Convertase Subtilisin/Kexin-Type 9 and Lipid Metabolism. Advances in Experimental Medicine and Biology, 2020(1276): 137–156.

Rademaker G, Hernandez G, Seo Y, et al., 2025, PCSK9 Drives Sterol-Dependent Metastatic Organ Choice in Pancreatic Cancer. Nature, 643(8074): 1381–1390.

Wong C, Wu J, Ji F, et al., 2022, The Cholesterol Uptake Regulator PCSK9 Promotes and is a Therapeutic Target in APC/KRAS-Mutant Colorectal Cancer. Nature Communications, 13(1): 3971.

Porcheron C, Le Devehat M, Roubtsova A, 2025, Blockade of Colon Cancer Metastasis via Single and Double Silencing of PCSK7/PCSK9: Enhanced T Cells Cytotoxicity in Mouse and Human. Journal for Immunotherapy of Cancer, 13(6): e011364.

Baek A, Nelson E, 2016, The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer. Hormones & Cancer, 7(4): 219–228.

Garcia-Estevez L, Moreno-Bueno G, 2019, Updating the Role of Obesity and Cholesterol in Breast Cancer. Breast Cancer Research: BCR, 21(1): 35.

Leignadier J, Dalenc F, Poirot M, et al., 2017, Improving the Efficacy of Hormone Therapy in Breast Cancer: The Role of Cholesterol Metabolism in SERM-Mediated Autophagy, Cell Differentiation and Death. Biochemical Pharmacology, 2017(144): 18–28.

Kitahara C, González A, Freedman N, et al., 2011, Total Cholesterol and Cancer Risk in a Large Prospective Study in Korea. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 29(12): 1592–1598.

Mu Y, Hao N, 2021, Detection and Clinical Significance of Serum PCSK9 and Blood Lipids Levels in Breast Cancer Patients. Journal of Modern Oncology, 29(15): 2633–2635.

Mei W, Tabrizi S, Godina C, et al., 2025, A Commonly Inherited Human PCSK9 Germline Variant Drives Breast Cancer Metastasis via LRP1 Receptor. Cell, 188(2): 371–389.

Scalambra L, Ruzzi F, Pittino O, et al., 2025, Targeting PCSK9, through an Innovative cVLP-based Vaccine, Enhanced the Therapeutic Activity of a cVLP-HER2 Vaccine in a Preclinical Model of HER2-Positive Mammary Carcinoma. Journal of Translational Medicine, 23(1): 136.

Wang L, Li S, Luo H, et al., 2022, PCSK9 Promotes the Progression and Metastasis of Colon Cancer Cells through Regulation of EMT and PI3K/AKT Signaling in Tumor Cells and Phenotypic Polarization of Macrophages. Journal of Experimental & Clinical Cancer Research: CR, 41(1): 303.

Zhang F, Shi Z, 2022, Progress in the Research of Hyperlipidemia and Lipid-Lowering Therapy in Malignant Tumors. Beijing Medical Journal, 44(11): 1027–1030.