{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:56Z","timestamp":1787028236103,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,21]],"date-time":"2024-01-21T00:00:00Z","timestamp":1705795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Scientific Research Project of Henan Province Colleges and Universities","award":["23B310002"],"award-info":[{"award-number":["23B310002"]}]},{"name":"Key Scientific Research Project of Henan Province Colleges and Universities","award":["202310472007"],"award-info":[{"award-number":["202310472007"]}]},{"name":"Key Scientific Research Project of Henan Province Colleges and Universities","award":["202210472052"],"award-info":[{"award-number":["202210472052"]}]},{"name":"National and Henan Province Innovation and Entrepreneurship Training Program for College Students of Xinxiang Medical University","award":["23B310002"],"award-info":[{"award-number":["23B310002"]}]},{"name":"National and Henan Province Innovation and Entrepreneurship Training Program for College Students of Xinxiang Medical University","award":["202310472007"],"award-info":[{"award-number":["202310472007"]}]},{"name":"National and Henan Province Innovation and Entrepreneurship Training Program for College Students of Xinxiang Medical University","award":["202210472052"],"award-info":[{"award-number":["202210472052"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Objective: This study explores the potential causal association between proprotein convertase subtilisin\/kexin 9 (PCSK9) inhibitors and tumor development using Mendelian randomization (MR) based on drug targets. Methods: Instrumental variables within \u00b1100 kb of the PCSK9 gene locus, impacting low-density lipoprotein cholesterol (LDL-C), were utilized for MR analysis. Coronary heart disease (CHD) served as a positive control to validate the causal relationship between PCSK9 inhibitors and various cancers. We employed reverse MR to address the reverse causation concerns. Data from positive controls and tumors were sourced from OpenGWAS. Results: MR analysis suggested a negative causal relationship between PCSK9 inhibitors and both breast and lung cancers (95%CIBreast cancer 0.81~0.99, p = 2.25 \u00d7 10\u22122; 95%CILung cancer 0.65~0.94, p = 2.55 \u00d7 10\u22123). In contrast, a positive causal link was observed with gastric, hepatic, and oral pharyngeal cancers and cervical intraepithelial neoplasia (95%CIGastric cancer 1.14~1.75, p = 1.88 \u00d7 10\u22122; 95%CIHepatic cancer 1.46~2.53, p = 1.16 \u00d7 10\u22122; 95%CIOral cavity and pharyngeal cancer 4.49~6.33, p = 3.36 \u00d7 10\u22124; 95%CICarcinoma in situ of cervix uteri 4.56~7.12, p = 6.91 \u00d7 10\u22123), without heterogeneity or pleiotropy (p &gt; 0.05). Sensitivity analyses confirmed these findings. The results of MR of drug targets suggested no causal relationship between PCSK9 inhibitors and bladder cancer, thyroid cancer, pancreatic cancer, colorectal cancer, malignant neoplasms of the kidney (except for renal pelvis tumors), malignant neoplasms of the brain, and malignant neoplasms of the esophagus (p &gt; 0.05). Reverse MR helped mitigate reverse causation effects. Conclusions: The study indicates a divergent causal relationship of PCSK9 inhibitors with certain cancers. While negatively associated with breast and lung cancers, a positive causal association was observed with gastric, hepatic, oral cavity, and pharyngeal cancers and cervical carcinoma in situ. No causal links were found with bladder, thyroid, pancreatic, colorectal, certain kidney, brain, and esophageal cancers.<\/jats:p>","DOI":"10.3390\/genes15010132","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T03:50:22Z","timestamp":1705895422000},"page":"132","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting"],"prefix":"10.3390","volume":"15","author":[{"given":"Wenxin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongrun","family":"Mi","sequence":"additional","affiliation":[{"name":"School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoyang","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Liu, J., Pandya, P., and Afshar, S. (2021). Therapeutic Advances in Oncology. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22042008"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lyu, J., Yang, E.J., and Shim, J.S. (2019). Cholesterol Trafficking: An Emerging Therapeutic Target for Angiogenesis and Cancer. Cells, 8.","DOI":"10.3390\/cells8050389"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.semcancer.2020.11.012","article-title":"LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies","volume":"73","author":"Revilla","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Murtola, T.J., Syv\u00e4l\u00e4, H., Pennanen, P., Bl\u00e4uer, M., Solakivi, T., Ylikomi, T., and Tammela, T.L.J. (2012). The Importance of LDL and Cholesterol Metabolism for Prostate Epithelial Cell Growth. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039445"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5253","DOI":"10.1002\/jcp.30229","article-title":"LDL cholesterol promotes the proliferation of prostate and pancreatic cancer cells by activating the STAT3 pathway","volume":"236","author":"Jung","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ioannidou, A., Watts, E.L., Perez-Cornago, A., Platz, E.A., Mills, I.G., Key, T.J., Travis, R.C., Tsilidis, K.K., and Zuber, V. (2022). The relationship between lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study. PLoS Med., 19.","DOI":"10.1371\/journal.pmed.1003859"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/cam4.695","article-title":"Blood lipids and prostate cancer: A Mendelian randomization analysis","volume":"5","author":"Bull","year":"2016","journal-title":"Cancer Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/s41391-017-0030-9","article-title":"Serum cholesterol and risk of high-grade prostate cancer: Results from the REDUCE study","volume":"21","author":"Jamnagerwalla","year":"2018","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1158\/1055-9965.EPI-14-1329","article-title":"Cholesterol Levels in Blood and the Risk of Prostate Cancer: A Meta-analysis of 14 Prospective Studies","volume":"24","author":"YuPeng","year":"2015","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"djv032","DOI":"10.1093\/jnci\/djv032","article-title":"Serum Lipids, Lipoproteins, and Risk of Breast Cancer: A Nested Case-Control Study Using Multiple Time Points","volume":"107","author":"Martin","year":"2015","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s10787-022-01077-w","article-title":"Statins block mammalian target of rapamycin pathway: A possible novel therapeutic strategy for inflammatory, malignant and neurodegenerative diseases","volume":"31","author":"Lashgari","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref_13","first-page":"141","article-title":"The role of statins in lung cancer","volume":"18","author":"Amin","year":"2022","journal-title":"Arch. Med. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.jacc.2022.05.041","article-title":"Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function","volume":"80","author":"Rosoff","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3971","DOI":"10.1038\/s41467-022-31663-z","article-title":"The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC\/KRAS-mutant colorectal cancer","volume":"13","author":"Wong","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1158\/0008-5472.CAN-11-0568","article-title":"Tumor Microenvironment\u2013Derived Proteins Dominate the Plasma Proteome Response during Breast Cancer Induction and Progression","volume":"71","author":"Pitteri","year":"2011","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"109513","DOI":"10.1016\/j.mehy.2019.109513","article-title":"Could PCSK9 be a new therapeutic target of Eugenol? In vitro and in silico evaluation of hypothesis","volume":"136","author":"Zia","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.jacl.2016.05.004","article-title":"Possible involvement of PCSK9 overproduction in hyperlipoproteinemia associated with hepatocellular carcinoma: A case report","volume":"10","author":"Nagashima","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"609663","DOI":"10.3389\/fonc.2020.609663","article-title":"Proprotein Convertase Subtilisin\/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation","volume":"10","author":"Xu","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bhattacharya, A., Chowdhury, A., Chaudhury, K., and Shukla, P.C. (2021). Proprotein convertase subtilisin\/kexin type 9 (PCSK9): A potential multifaceted player in cancer. Biochim. Biophys. Acta (BBA)\u2014Rev. Cancer, 1876.","DOI":"10.1016\/j.bbcan.2021.188581"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chong, E.W., Joncas, F.-H., Seidah, N.G., Calon, F., Diorio, C., and Gangloff, A. (2022). Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancers. BMC Cancer, 22.","DOI":"10.21203\/rs.3.rs-1420016\/v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.clinbiochem.2019.11.001","article-title":"Plasma proteomics-based identification of novel biomarkers in early gastric cancer","volume":"76","author":"Zhou","year":"2020","journal-title":"Clin. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.5114\/aoms.2020.91291","article-title":"Effects of immunisation against PCSK9 in mice bearing melanoma","volume":"16","author":"Nik","year":"2020","journal-title":"Arch. Med. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"175721","DOI":"10.1016\/j.ejphar.2023.175721","article-title":"The evolving landscape of PCSK9 inhibition in cancer","volume":"949","author":"Oza","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1002\/hep4.1858","article-title":"Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol","volume":"6","author":"Ioannou","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Richardson, T.G., Sanderson, E., Palmer, T.M., Ala-Korpela, M., Ference, B.A., Smith, G.D., and Holmes, M.V. (2020). Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med., 17.","DOI":"10.1371\/journal.pmed.1003062"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1002\/art.42304","article-title":"Telomere Length and Development of Systemic Lupus Erythematosus: A Mendelian Randomization Study","volume":"74","author":"Wang","year":"2022","journal-title":"Arthritis Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13075-023-03122-7","article-title":"Causal relationship between PCSK9 inhibitor and autoimmune diseases: A drug target Mendelian randomization study","volume":"25","author":"Xie","year":"2023","journal-title":"Arthritis Res. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"50630","DOI":"10.1074\/jbc.M410077200","article-title":"Post-transcriptional Regulation of Low Density Lipoprotein Receptor Protein by Proprotein Convertase Subtilisin\/Kexin Type 9a in Mouse Liver","volume":"279","author":"Park","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s11910-022-01197-4","article-title":"Lipid-Modifying Therapies and Stroke Prevention","volume":"22","author":"Hackam","year":"2022","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173114","DOI":"10.1016\/j.ejphar.2020.173114","article-title":"Statins and PCSK9 inhibitors: A new lipid-lowering therapy","volume":"878","author":"Daum","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.celrep.2016.03.020","article-title":"Tumor-Induced Hyperlipidemia Contributes to Tumor Growth","volume":"15","author":"Huang","year":"2016","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104847","DOI":"10.1016\/j.phrs.2020.104847","article-title":"Pseurotin A as a novel suppressor of hormone dependent breast cancer progression and recurrence by inhibiting PCSK9 secretion and interaction with LDL receptor","volume":"158","author":"Abdelwahed","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_34","first-page":"00469580221096259","article-title":"Bioinformatics Identification of Key Genes for the Development and Prognosis of Lung Adenocarcinoma","volume":"59","author":"Luo","year":"2022","journal-title":"Inq. J. Health Care Organ. Provis. Financ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/prca.201200069","article-title":"SILAC-based quantitative proteomic analysis of gastric cancer secretome","volume":"7","author":"Marimuthu","year":"2012","journal-title":"Proteom. Clin. Appl."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Alannan, M., Fatrouni, H., Tr\u00e9z\u00e9guet, V., Dittrich-Domergue, F., Moreau, P., Siegfried, G., Liet, B., Khatib, A.-M., Grosset, C.F., and Badran, B. (2022). Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis. Cells, 12.","DOI":"10.3390\/cells12010062"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"90","DOI":"10.20892\/j.issn.2095-3941.2020.0313","article-title":"Protein convertase subtilisin\/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway","volume":"18","author":"He","year":"2021","journal-title":"Cancer Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15228","DOI":"10.18632\/aging.205347","article-title":"Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: A drug-target Mendelian randomization study","volume":"15","author":"Chen","year":"2023","journal-title":"Aging"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"EBioMedicine (2015). PCSK9 Inhibitors: What Lies Beyond Monoclonal Antibodies?. eBioMedicine, 2.","DOI":"10.1016\/j.ebiom.2015.12.006"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/joim.12614","article-title":"Can LDL cholesterol be too low? Possible risks of extremely low levels","volume":"281","author":"Olsson","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1201454","DOI":"10.3389\/fgene.2023.1201454","article-title":"Editorial: Functional screening for cancer drug discovery: From experimental approaches to data integration","volume":"14","author":"Zhou","year":"2023","journal-title":"Front. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/132\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:46:35Z","timestamp":1760103995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/132"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,21]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["genes15010132"],"URL":"https:\/\/doi.org\/10.3390\/genes15010132","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,21]]}}}