{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:54:11Z","timestamp":1780509251897,"version":"3.54.1"},"reference-count":149,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The accumulation of high levels of cholesterol associated with low-density lipoprotein (LDL) in the bloodstream is the key risk factor for stroke and cardiovascular diseases. Therefore, reducing the concentration of LDL-cholesterol in the blood and maintaining it at an optimum level are vital especially for hypercholesterolemic individuals and cardiovascular patients. Thus, the study of cholesterol management and regulation in the physiological system has drawn significant attention from researchers across the globe. This led to the discovery of several cholesterol-lowering drugs which have been approved for administration either via oral or non-oral routes. Owing to the high comfort level, reduced or no pain, and fewer side effects with oral administration, more focus has been directed towards the development of oral-based cholesterol-lowering drugs. The other modes of administration such as intravenous or intramuscular injections are complex and sometimes painful and less tolerable. Therefore, there was a significant interest to develop oral drugs targeting PCSK9. In fact, some progress has been accomplished in recent years. This review provides an overview of the existing cholesterol-lowering drugs, and the progress made so far with oral-based PCSK9 drugs for lowering LDL-cholesterol. The review is presented in several sections highlighting the molecular targets, the individual drugs, and the modes of administration, with a focus on the oral route.<\/jats:p>","DOI":"10.3390\/biom15040468","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:48:20Z","timestamp":1742824100000},"page":"468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Oral and Non-Oral Cholesterol-Lowering Drugs with PCSK9 and Other Biomolecules as Targets: Present Status and Future Prospects"],"prefix":"10.3390","volume":"15","author":[{"given":"Ajoy","family":"Basak","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"History in medicine: The story of cholesterol, lipids and cardiology","volume":"19","author":"Kuijper","year":"2021","journal-title":"e-J. Cardiol. Pract. (Eur. Soc. Cardiol.)"},{"key":"ref_2","unstructured":"Huff, T., Boyd, B., and Jialal, I. (2025, March 11). Physiology, Cholesterol. [Updated 6 March 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK470561\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.4158\/EP-2020-0347","article-title":"Cholesterol Review: A Metabolically Important Molecule","volume":"26","author":"Schade","year":"2020","journal-title":"Endocr. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zampelas, A., and Magriplis, E. (2019). New Insights into Cholesterol Functions: A Friend or an Enemy?. Nutrients, 11.","DOI":"10.3390\/nu11071645"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-022-01125-5","article-title":"Regulation of cholesterol homeostasis in health and diseases: From mechanisms to targeted therapeutics","volume":"7","author":"Duan","year":"2022","journal-title":"Sig. Transduct. Target Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1146\/annurev-biochem-062917-011852","article-title":"Retrospective on Cholesterol Homeostasis: The Central Role of Scap","volume":"87","author":"Brown","year":"2018","journal-title":"Annu. Rev. Biochem."},{"key":"ref_7","first-page":"52","article-title":"Cholesterol and its implications","volume":"5","author":"Idoko","year":"2020","journal-title":"Univers. J. Pharm. Research."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S0889-8529(05)70023-2","article-title":"Lipoprotein Physiology","volume":"27","author":"Ginsberg","year":"1998","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1067\/mnc.2002.128959","article-title":"The physiology of lipoproteins","volume":"9","author":"Tulenko","year":"2002","journal-title":"J. Nucl. Cardiol."},{"key":"ref_10","unstructured":"Feingold, K.R., Anawalt, B., and Blackman, M.R. (2025, February 07). Introduction to Lipids and Lipoproteins. [Updated 14 January 2024], Endotext [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK305896\/."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"474","DOI":"10.7150\/ijbs.5.474","article-title":"Lipoproteins, cholesterol homeostasis and cardiac health","volume":"5","author":"Daniels","year":"2009","journal-title":"Int. J. Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2020.07.019","article-title":"Lipoproteins and lipids in cardiovascular disease: From mechanistic insights to therapeutic targeting","volume":"159","author":"Soppert","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S156","DOI":"10.1194\/jlr.R800058-JLR200","article-title":"Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall","volume":"50","author":"Getz","year":"2009","journal-title":"J Lipid Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5483","DOI":"10.1021\/acs.biochem.6b00342","article-title":"Cholesterol Biosynthesis: A Mechanistic Overview","volume":"55","author":"Cerqueira","year":"2016","journal-title":"Biochemistry"},{"key":"ref_15","unstructured":"National Center for Biotechnology Information (2025, February 07). PubChem Pathway Summary for Pathway SMP0121057, Bloch Pathway (Cholesterol Biosynthesis). Source: PathBank, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/pathway\/PathBank:SMP0121057."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.bcp.2013.03.021","article-title":"A comprehensive machine-readable view of the mammalian cholesterol biosynthesis pathway","volume":"86","author":"Mazein","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1111\/febs.15727","article-title":"Cholesterol metabolism pathways are the intermediates more important than the products?","volume":"288","author":"Wang","year":"2021","journal-title":"FEBS J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/j.numecd.2020.12.032","article-title":"The effects of foods on LDL cholesterol levels: A systematic review of the accumulated evidence from systematic reviews and meta-analyses of randomized controlled trials","volume":"31","author":"Schoeneck","year":"2021","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1161\/CIR.0000000000000743","article-title":"Dietary Cholesterol and Cardiovascular Risk: A Science Advisory from the American Heart Association","volume":"141","author":"Carson","year":"2020","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Soliman, G.A. (2018). Dietary Cholesterol and the Lack of Evidence in Cardiovascular Disease. Nutrients, 10.","DOI":"10.3390\/nu10060780"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.jacl.2015.11.010","article-title":"A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality","volume":"10","author":"Wadhera","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1016\/j.cmet.2021.09.001","article-title":"Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases","volume":"33","author":"Song","year":"2021","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"200","DOI":"10.2174\/157016111794519354","article-title":"Hypocholesterolemia","volume":"9","author":"Moutzouri","year":"2011","journal-title":"Curr. Vasc. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2188\/jea.JE20100065","article-title":"Low cholesterol is associated with mortality from stroke, heart disease, and cancer: The Jichi Medical School Cohort Study","volume":"21","author":"Nago","year":"2011","journal-title":"J. Epidemiol."},{"key":"ref_25","first-page":"26","article-title":"Health risks of very low cholesterol","volume":"5","author":"Nagar","year":"2011","journal-title":"Sci. J. Lander Coll. Arts Sci."},{"key":"ref_26","unstructured":"(2025, February 07). Available online: https:\/\/www.who.int\/data\/gho\/indicator-metadata-registry\/imr-details\/3236#:~:text=Globally%2C%20a%20third%20of%20ischaemic,or%202%25%20of%20total%20DALYS."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5334\/gh.1288","article-title":"The Heart of the World","volume":"19","author":"Perel","year":"2024","journal-title":"Glob. Heart"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/j.jacc.2022.11.001","article-title":"Global Burden of Cardiovascular Diseases and Risks Collaboration, 1990\u20132021","volume":"80","author":"Lindstrom","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5138","DOI":"10.1038\/s41467-018-07590-3","article-title":"Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol","volume":"9","author":"Jiang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Friesen, J.A., and Rodwell, V.W. (2004). The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biol., 5.","DOI":"10.1186\/gb-2004-5-11-248"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrd1112","article-title":"Lovastatin and beyond: The history of the HMG-CoA reductase inhibitors","volume":"2","author":"Tobert","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_32","unstructured":"Bansal, A.B., and Cassagnol, M. (2025, March 11). HMG-CoA Reductase Inhibitors. [Updated 3 July 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK542212\/."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1016\/S0140-6736(16)31357-5","article-title":"Interpretation of the evidence for the efficacy and safety of statin therapy","volume":"388","author":"Collins","year":"2016","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41569-018-0098-5","article-title":"Safety and efficacy of statin therapy","volume":"15","author":"Adhyaru","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1093\/eurjpc\/zwab171","article-title":"Statin therapy and lipoprotein(a) levels: A systematic review and meta-analysis","volume":"29","author":"Oorthuys","year":"2022","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1001\/jama.2022.12138","article-title":"Statin Use for the Primary Prevention of Cardiovascular Disease in Adults Updated Evidence Report and Systematic Review for the US Preventive Services Task Force","volume":"328","author":"Chou","year":"2022","journal-title":"JAMA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e389","DOI":"10.1161\/CIRCULATIONAHA.114.013189","article-title":"Statin Intolerance","volume":"131","author":"Fitchett","year":"2015","journal-title":"Circulation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1073\/pnas.0335507100","article-title":"The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation","volume":"100","author":"Seidah","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"575","DOI":"10.2174\/092986612800494020","article-title":"Proprotein Convertase Subtilisin Kexin9 (PCSK9): A Novel Target for Cholesterol Regulation","volume":"19","author":"Basak","year":"2012","journal-title":"Prot. Pep. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-023-01690-3","article-title":"Targeting proprotein convertase subtilisin\/kexin type 9 (PCSK9): From bench to bedside","volume":"9","author":"Bao","year":"2024","journal-title":"Sig. Transduct. Target Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1097\/MOL.0000000000000114","article-title":"PCSK9 and LDLR degradation: Regulatory mechanisms in circulation and in cells","volume":"25","author":"Lagace","year":"2014","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s44161-022-00085-x","article-title":"Chasing LDL cholesterol to the bottom-PCSK9 in perspective","volume":"1","author":"Libby","year":"2022","journal-title":"Nat. Cardiovasc. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1210\/endrev\/bnab035","article-title":"The Multifaceted Biology of PCSK9","volume":"43","author":"Seidah","year":"2022","journal-title":"Endocr. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.jacl.2015.01.002","article-title":"Adenosine triphosphate citrate lyase: Emerging target in the treatment of dyslipidemia","volume":"9","author":"Lemus","year":"2015","journal-title":"J. Clin. Lipidol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"211","DOI":"10.2174\/1568013033483357","article-title":"ATP-citrate Lyase: A Potential Target for Hypolipidemic Intervention","volume":"3","author":"Groot","year":"2003","journal-title":"Curr. Med. Chem.-Immunol. Endocr. Metab. Agents"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4875","DOI":"10.1021\/jm00104a014","article-title":"ATP-citrate lyase as a target for hypolipidemic intervention. Sulfoximine and 3-hydroxy-beta-lactam containing analogues of citric acid as potential tight-binding inhibitors","volume":"35","author":"Dolle","year":"1992","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2165\/00003495-200767010-00002","article-title":"Squalene synthase inhibitors: Clinical pharmacology and cholesterol-lowering potential","volume":"67","author":"Durrington","year":"2007","journal-title":"Drugs"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"101033","DOI":"10.1016\/j.plipres.2020.101033","article-title":"Squalene monooxygenase: A journey to the heart of cholesterol synthesis","volume":"79","author":"Chua","year":"2020","journal-title":"Prog. Lipid Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.tips.2005.05.004","article-title":"Lord of the rings\u2014The mechanism for oxidosqualene:lanosterol cyclase becomes crystal clear","volume":"26","author":"Huff","year":"2005","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Long, T., Debler, E.W., and Li, X. (2022). Structural enzymology of cholesterol biosynthesis and storage. Curr. Opin. Struct. Biol., 74.","DOI":"10.1016\/j.sbi.2022.102369"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1080\/09168451.2020.1793658","article-title":"Recent advances in regulating cholesterol and bile acid metabolism","volume":"84","author":"Sato","year":"2020","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S237","DOI":"10.2337\/dc09-S355","article-title":"Bile acids and metabolic regulation: Mechanisms and clinical responses to bile acid sequestration","volume":"32","author":"Staels","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_53","first-page":"1","article-title":"Bile acid metabolism and signaling in health and disease: Molecular mechanisms and therapeutic targets","volume":"9","author":"Fleishman","year":"2024","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_54","first-page":"24","article-title":"Bile Acids: The Good, the Bad, and the Ugly","volume":"14","author":"Hofmann","year":"1999","journal-title":"News Physiol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1097\/00001574-200203000-00017","article-title":"Cholesterol absorption","volume":"18","author":"Ostlund","year":"2002","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_56","unstructured":"Patel, V.B. (2019). Chapter 5\u2014An Overview of Cholesterol Absorption. The Molecular Nutrition of Fats, Elsevier."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E17","DOI":"10.1016\/S1520-765X(01)90108-7","article-title":"Cholesterol absorption inhibition: Filling an unmet need in lipid-lowering management","volume":"3","author":"Leitersdorf","year":"2001","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.jacl.2010.08.015","article-title":"Novel therapies and new targets of treatment for familial hypercholesterolemia","volume":"4","author":"Goldberg","year":"2010","journal-title":"J. Clin. Lipidol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Kounatidis, D., Vallianou, N.G., Poulaki, A., Evangelopoulos, A., Panagopoulos, F., Stratigou, T., Geladari, E., Karampela, I., and Dalamaga, M. (2024). ApoB100 and Atherosclerosis: What\u2019s New in the 21st Century?. Metabolites, 14.","DOI":"10.3390\/metabo14020123"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2217\/clp.11.21","article-title":"Regulation of microsomal triglyceride transfer protein","volume":"6","author":"Hussain","year":"2011","journal-title":"Clin Lipidol."},{"key":"ref_61","first-page":"78","article-title":"Hyperlipidemia: Drugs for Cardiovascular Risk Reduction in Adults","volume":"95","author":"Last","year":"2017","journal-title":"Am Fam Physician."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1016\/j.cjca.2024.05.004","article-title":"Medications for Lipid Control: Statins vs Newer Drugs","volume":"40","author":"McPherson","year":"2024","journal-title":"Can. J. Cardiol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Ma, W., Pan, Q., Pan, D., Xu, T., Zhu, H., and Li, D. (2021). Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.713007"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2","DOI":"10.56095\/eaj.v1i1.7","article-title":"The pharmacology of cholesterol-lowering drugs","volume":"1","author":"Ballantyne","year":"2022","journal-title":"Eur. Atheroscler. J."},{"key":"ref_65","unstructured":"Sizar, O., Khare, S., Patel, P., and Talati, R. (2025, March 11). Statin Medications. [Updated 29 February 2024], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK430940\/."},{"key":"ref_66","first-page":"1","article-title":"Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease","volume":"16","author":"Pignone","year":"2023","journal-title":"UpToDate"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1001\/jama.2022.13044","article-title":"Statin Use for the Primary Prevention of Cardiovascular Disease in Adults","volume":"328","author":"Mangione","year":"2022","journal-title":"JAMA."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e305","DOI":"10.1016\/S2214-109X(21)00572-6","article-title":"Statins: Are they appropriate for all patients?","volume":"10","author":"Raal","year":"2022","journal-title":"Lancet Glob. Health"},{"key":"ref_69","first-page":"631","article-title":"Statin Therapy: Review of Safety and Potential Side Effects","volume":"32","author":"Ramkumar","year":"2016","journal-title":"Acta Cardiol. Sin."},{"key":"ref_70","unstructured":"(2025, February 07). Statins Market Size to Hit US $22 Billion by 2032, Owing to Increasing Investments in Healthcare Sector Globally. Persistence Market Research. 2 March 2023. Available online: https:\/\/www.globenewswire.com\/news-release\/2023\/03\/02\/2619166\/0\/en\/Statins-Market-Size-To-Hit-US-22-Billion-By-2032-Owing-To-Increasing-Investments-in-Healthcare-Sector-Globally-Persistence-Market-Research.html."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"484","DOI":"10.2183\/pjab.86.484","article-title":"A historical perspective on the discovery of statins","volume":"86","author":"Endo","year":"2010","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Climent, E., Benaiges, D., and Pedro-Botet, J. (2021). Hydrophilic or Lipophilic Statins?. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.687585"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e2135371","DOI":"10.1001\/jamanetworkopen.2021.35371","article-title":"Trends in Use and Expenditures for Brand-name Statins After Introduction of Generic Statins in the US, 2002\u20132018","volume":"4","author":"Lin","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.medcli.2017.11.030","article-title":"Statins: Pros and cons","volume":"150","author":"Mammen","year":"2018","journal-title":"Med. Clin. (Barc)"},{"key":"ref_75","first-page":"1","article-title":"Statins","volume":"384","author":"Kulkarni","year":"2024","journal-title":"BMJ"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s40265-020-01308-w","article-title":"Bempedoic Acid: First Approval","volume":"80","author":"Markham","year":"2020","journal-title":"Drugs"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e141221198875","DOI":"10.2174\/1573403X17666211214111658","article-title":"An Update on New Cholesterol Inhibitor: Bempedoic Acid","volume":"18","author":"Kulshreshtha","year":"2022","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1056\/NEJMoa2215024","article-title":"for CLEAR Outcomes Investigators. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients","volume":"380","author":"Nissen","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_79","unstructured":"Sizar, O., Nassereddin, A., and Talati, R. (2025, March 11). Ezetimibe. [Updated 28 August 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK532879\/."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/jm030283g","article-title":"The discovery of ezetimibe: A view from outside the receptor","volume":"47","author":"Clader","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_81","first-page":"415","article-title":"Ezetimibe therapy: Mechanism of action and clinical update","volume":"8","author":"Phan","year":"2012","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s11892-009-0087-5","article-title":"Bile Acid Sequestrants for Lipid and Glucose Control","volume":"10","author":"Staels","year":"2010","journal-title":"Curr. Diab. Rep."},{"key":"ref_83","unstructured":"(2025, March 11). Colestipol. [Updated 28 September 2017], LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK548432\/."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"161","DOI":"10.2165\/00003495-198019030-00001","article-title":"Colestipol: A review of its pharmacological properties and therapeutic efficacy in patients with hypercholesterolaemia","volume":"19","author":"Heel","year":"1980","journal-title":"Drugs"},{"key":"ref_85","unstructured":"Patel, P.H., and Can, A.S. (2025, March 11). Colesevelam. [Updated 1 May 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK557815\/."},{"key":"ref_86","first-page":"733","article-title":"Colesevelam hydrochloride: Reducing atherosclerotic coronary heart disease risk factors","volume":"3","author":"Bays","year":"2007","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_87","first-page":"321","article-title":"Colesevelam (WelChol) for Reduction of LDL Cholesterol","volume":"72","author":"Radosh","year":"2005","journal-title":"Am. Fam. Phys."},{"key":"ref_88","unstructured":"Riaz, S., and John, S. (2025, March 11). Cholestyramine Resin. [Updated 8 May 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK534089\/."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s11739-011-0653-0","article-title":"Use and indications of cholestyramine and bile acid sequestrants","volume":"8","author":"Scaldaferri","year":"2013","journal-title":"Intern. Emerg. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/sj.bjp.0705332","article-title":"Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro","volume":"139","author":"Nishimoto","year":"2003","journal-title":"Br. J. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"18750","DOI":"10.1074\/jbc.M112.351254","article-title":"Binding Modes of Zaragozic Acid A to Human Squalene Synthase and Staphylococcal Dehydrosqualene Synthase","volume":"287","author":"Liu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0163-7827(02)00029-2","article-title":"Squalene epoxidase as hypocholesterolemic drug target revisited","volume":"42","author":"Chugh","year":"2003","journal-title":"Prog. Lipid Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1515\/BC.2011.195","article-title":"Squalene monooxygenase\u2014A target for hypercholesterolemic therapy","volume":"392","author":"Belter","year":"2011","journal-title":"Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"74","DOI":"10.4103\/HEARTVIEWS.HEARTVIEWS_59_19","article-title":"PCSK 9 Inhibitors: A Short History and a New Era of Lipid-lowering Therapy","volume":"20","author":"Hajar","year":"2019","journal-title":"Heart Views"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/10742484221100107","article-title":"Comprehensive Review of PCSK9 Inhibitors","volume":"27","author":"Coppinger","year":"2022","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_96","first-page":"1","article-title":"PCSK9 inhibitors: Current status and emerging frontiers","volume":"23","author":"Agnello","year":"2023","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_97","first-page":"123","article-title":"Praluent (Alirocumab): First PCSK9 Inhibitor Approved by the FDA for Hypercholesterolemia","volume":"9","author":"Raedler","year":"2016","journal-title":"Am. Health Drug Benefits"},{"key":"ref_98","first-page":"28","article-title":"Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors","volume":"41","author":"Manniello","year":"2016","journal-title":"Pharm. Ther."},{"key":"ref_99","first-page":"136","article-title":"Repatha (Evolocumab): Second PCSK9 Inhibitor Approved by the FDA for Patients with Familial Hypercholesterolemia","volume":"9","author":"Fala","year":"2016","journal-title":"Am. Health Drug Benefits"},{"key":"ref_100","first-page":"641","article-title":"A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab","volume":"22","author":"McDonagh","year":"2016","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1056\/NEJMoa1105803","article-title":"Effect of a monoclonal antibody to PCSK9 on LDL cholesterol","volume":"366","author":"Stein","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.jacc.2012.08.986","article-title":"Effects of AMG145 on low-density lipoprotein cholesterol levels: Results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins","volume":"60","author":"Dias","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1056\/NEJMoa1614062","article-title":"Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab","volume":"376","author":"Ridker","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_104","unstructured":"Adams, B. (2025, February 07). Pfizer Dumps PCSK9 Inhibitor Bococizumab After Finding \u2019no Value\u2019 in Drug. Fierce Biotech Questex. Available online: https:\/\/www.fiercebiotech.com\/biotech\/pfizer-dumps-pcsk9i-inhibitor-bococizumab-after-finding-no-value-med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S2213-8587(22)00353-9","article-title":"Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): Results from the 4-year open-label extension of the ORION-1 trial","volume":"11","author":"Ray","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_106","first-page":"8129513","article-title":"Advantages and Disadvantages of Inclisiran: A Small Interfering Ribonucleic Acid Molecule Targeting PCSK9-A Narrative Review","volume":"2022","author":"Reiner","year":"2022","journal-title":"Cardiovasc. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e032031","DOI":"10.1161\/JAHA.123.032031","article-title":"Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story of Inclisiran","volume":"13","author":"Wilkinson","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s40256-022-00534-9","article-title":"Cost Effectiveness of Inclisiran in Atherosclerotic Cardiovascular Patients with Elevated Low-Density Lipoprotein Cholesterol Despite Statin Use: A Threshold Analysis","volume":"22","author":"Desai","year":"2022","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1194\/jlr.P082834","article-title":"Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects","volume":"59","author":"Nandakumar","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1093\/eurheartj\/ehs023","article-title":"Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: A randomized, double-blind, placebo-controlled trial","volume":"33","author":"Visser","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_111","unstructured":"Hamada, M., and Farzam, K. (2025, March 11). Mipomersen. [Updated 2 July 2023], StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK592392\/."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1186\/s13023-024-03374-9","article-title":"Long-term effectiveness and safety of lomitapide in patients with homozygous familial hypercholesterolemia: An observational case series","volume":"19","author":"Suppressa","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/s41419-022-05075-2","article-title":"RNA-based therapeutics: An overview and prospectus","volume":"13","author":"Zhu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4272","DOI":"10.1093\/eurheartj\/ehad596","article-title":"LIBerate-HeFH investigators. Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: The LIBerate-HeFH trial","volume":"44","author":"Raal","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.atherosclerosis.2023.06.948","article-title":"Randomized, open-label, cross-over, phase-3 study to evaluate efficacy and safety of LIB003 compared with evolocumab in homozygous familial hypercholesterolaemia patients on stable lipid-lowering therapy (liberate-HOFH)","volume":"379","author":"Raal","year":"2023","journal-title":"Atherosclerosis"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S2213-8587(17)30060-8","article-title":"Limitations of cholesterol lowering with PCSK9 inhibitors","volume":"5","author":"Thompson","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_117","first-page":"191","article-title":"Safety and Tolerability of PCSK9 Inhibitors: Current Insights","volume":"12","author":"Kosmas","year":"2020","journal-title":"Clin. Pharmacol."},{"key":"ref_118","first-page":"1","article-title":"Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS","volume":"13","author":"Zhen","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.athplu.2024.11.003","article-title":"Emerging oral therapeutic strategies for inhibiting PCSK9","volume":"59","author":"Ferri","year":"2024","journal-title":"Atheroscler. Plus"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"118514","DOI":"10.1016\/j.atherosclerosis.2024.118514","article-title":"AZD0780, the first oral small molecule PCSK9 inhibitor for the treatment of hypercholesterolemia: Results from a randomized, single-blind, placebo-controlled phase 1 trial","volume":"395","author":"Vega","year":"2024","journal-title":"Atherosclerosis"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1080\/13543784.2023.2267972","article-title":"MK-0616: An oral PCSK9 inhibitor for hypercholesterolemia treatment","volume":"32","author":"Burnett","year":"2023","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_122","unstructured":"(2025, February 07). Available online: https:\/\/www.pharmaceutical-technology.com\/data-insights\/azd-0780-astrazeneca-cardiovascular-disease-likelihood-of-approval\/."},{"key":"ref_123","unstructured":"(2025, February 07). A Study to Assess the Efficacy, Safety and Tolerability of Different Doses of AZD0780 in Patients with Dyslipidemia (PURSUIT), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06173570?rank=1."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"eabe9117","DOI":"10.1126\/scitranslmed.abe9117","article-title":"An oral antisense oligonucleotide for PCSK9 inhibition","volume":"13","author":"Gennemark","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1124\/dmd.123.001370","article-title":"In Vivo Metabolite Profiles of an N-Acetylgalactosamine-Conjugated Antisense Oligonucleotide AZD8233 Using Liquid Chromatography High-Resolution Mass Spectrometry: A Cross-Species Comparison in Animals and Humans","volume":"51","author":"Li","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Mohamed, F., Mansfield, B., and Raal, F.J. (2023). Targeting PCSK9 and Beyond for the Management of Low-Density Lipoprotein Cholesterol. J. Clin. Med., 12.","DOI":"10.3390\/jcm12155082"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/S2213-8587(23)00325-X","article-title":"PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: A randomised, double-blind, placebo-controlled and active-controlled phase 2 trial","volume":"12","author":"Koren","year":"2024","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_128","unstructured":"(2025, February 07). Available online: https:\/\/sciencehub.novonordisk.com\/content\/dam\/hcpexperience\/kol\/en\/publications\/pmid_38310920\/documents\/koren-et-al-oral-pcsk9i-phase-2.pdf."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Sawyer, T.K., and Biswas, K. (2022). Chapter 1, Peptide Drug Discovery Raison d\u2019Etre: Engineering Mindset, Design Rules and Screening Tools. Approaching the Next Inflection in Peptide Therapeutics: Attaining Cell Permeability and Oral Bioavailability, American Chemical Society.","DOI":"10.1021\/bk-2022-1417.ch001"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"A12579","DOI":"10.1161\/circ.142.suppl_3.12579","article-title":"CVI-LM001, a first-in-class novel oral PCSK9 modulator, lowers plasma Ldl-c and reduces circulating PCSK9 in preclinical animal models and in hyperlipidemic human subjects","volume":"142","author":"Liu","year":"2020","journal-title":"Circulation"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.cmet.2022.03.006","article-title":"Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial","volume":"34","author":"Wang","year":"2022","journal-title":"Cell. Metab."},{"key":"ref_132","first-page":"125","article-title":"Molecular Docking Studies of Berberine Derivatives as Novel Multitarget PCSK9 and HMGCR Inhibitors","volume":"37","author":"Jaitrong","year":"2021","journal-title":"SWU Sci. J."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/j.jacc.2023.02.018","article-title":"Phase 2b randomized trial of the oral PCSK9 inhibitor MK-0616","volume":"81","author":"Ballantyne","year":"2023","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S2213-8587(23)00358-3","article-title":"An anti-PCSK9 pill a day to keep cholesterol away: Next steps?","volume":"12","author":"Watts","year":"2024","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1161\/CIRCULATIONAHA.122.063372","article-title":"Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low-Density Lipoprotein Receptor","volume":"148","author":"Johns","year":"2023","journal-title":"Circulation"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"9227","DOI":"10.1021\/acs.jmedchem.3c01112","article-title":"Correction to Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia treatment","volume":"66","author":"Ahmed","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"155073","DOI":"10.1016\/j.tetlet.2024.155073","article-title":"A novel method for the synthesis of macrocyclic peptides using arylsulfonyloxyacetic acids as N-terminus functional groups","volume":"141","author":"Kobayashi","year":"2024","journal-title":"Tetrahedron Lett."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/d41573-023-00152-3","article-title":"Macrocycle drugs serve up new opportunities","volume":"22","author":"Kingwell","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.ejmech.2015.01.022","article-title":"LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (aa153-421): Design, synthesis and biochemical evaluation","volume":"92","author":"Alghamdi","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_140","unstructured":"Alghamdi, R.H. (2013). Development of Inhibitors of Human PCSK9 as Potential Regulators of LDL-Receptor and Cholesterol. [Master\u2019s Thesis, Principal Supervisor: Ajoy Basak + co-supervisor: Tom Lagace, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa]. Available online: https:\/\/ruor.uottawa.ca\/items\/25aa5b31-0216-4f72-a067-41790829ea7d."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.atherosclerosis.2021.06.903","article-title":"The emerging landscape of peptide-based inhibitors of PCSK9","volume":"330","author":"Tombling","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s11883-024-01199-2","article-title":"Oral PCSK9 Inhibitors","volume":"26","author":"Agarwala","year":"2024","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_143","unstructured":"Basak, A. (2016). Peptides Derived from Human PCSK9 Catalytic Domain & Its Uses Thereof for Promoting LDL-R Activity. (WO2016\/119067 A1), WO Patent, Available online: https:\/\/patentscope.wipo.int\/search\/en\/detail.jsf?docId=WO2016119067&redirectedID=true."},{"key":"ref_144","unstructured":"Basak, A. (2018). Peptides Derived from Human PCSK9 Catalytic Domain & Their Uses Thereof for Promoting LDL-R Activity. (US 2018\/0023071 A1), US Patent."},{"key":"ref_145","unstructured":"(2025, February 07). Aqur Biosciences, Inc., Westlake Village, CA, USA. Available online: www.aqurbiosciences.com."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/S0022-3476(06)80136-8","article-title":"Treatment of severe familial hypercholesterolemia in childhood with sitosterol and sitostanol","volume":"122","author":"Becker","year":"1993","journal-title":"J. Pediatr."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Bardolia, C., Shah, A.N., and Turgeon, J. (2021). Emerging Non-statin Treatment Options for Lowering Low-Density Lipoprotein Cholesterol. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.789931"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/d41573-021-00093-9","article-title":"Pushing the envelope with PCSK9","volume":"20","author":"Kingwell","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/MOL.0000000000000919","article-title":"PCSK9-directed therapies: An update","volume":"35","author":"Katzmann","year":"2024","journal-title":"Current Opinion in Lipidology."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/468\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:58:27Z","timestamp":1760029107000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/4\/468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,22]]},"references-count":149,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["biom15040468"],"URL":"https:\/\/doi.org\/10.3390\/biom15040468","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,22]]}}}