{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:13:42Z","timestamp":1787508822564,"version":"build-2736575974"},"reference-count":48,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Science Progress"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:p>This narrative review comprehensively examines the multifaceted roles of proprotein convertase subtilisin\/kexin type 9 (PCSK9) in peripheral arterial disease (PAD). PCSK9, a key enzymatic regulator of lipid metabolism, binds to low-density lipoprotein receptors (LDLRs) and promotes their degradation, thereby increasing plasma low-density lipoprotein cholesterol (LDL-C) levels. This mechanism establishes PCSK9 as a critical driver of atherosclerosis and PAD. Emerging evidence indicates that the role of PCSK9 in PAD extended beyond its traditional lipid-modulating functions. Specifically, PCSK9 gene polymorphisms have been shown to significantly increase PAD susceptibility, while elevated plasma PCSK9 is an independent PAD risk factor and correlates positively with disease severity. Mechanistic studies revealed that PCSK9 directly participated in vascular pathological processes through multiple pathways, some of which are independent of LDLR-mediated effects. Current clinical applications have demonstrated that PCSK9 inhibitors confer clinically meaningful therapeutic benefits in PAD patients, including reduced risks of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). In particular, some of these clinical benefits may be attributed to improvements in endothelial function and microcirculatory perfusion. However, the therapeutic strategies involving PCSK9 inhibitors face persistent challenges, such as determining optimal dosing timelines, assessing long-term safety, and exploring synergies with other therapies. Future studies should prioritize large-scale randomized controlled trials to elucidate the molecular mechanisms underlying PCSK9's roles in vascular calcification and inflammatory microenvironments. Additionally, advancing the precision interventions targeting PCSK9 is essential for advancing comprehensive management approaches for PAD.<\/jats:p>","DOI":"10.1177\/00368504251370679","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T18:10:57Z","timestamp":1758046257000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["PCSK9 in peripheral arterial disease: Mechanisms and therapeutic perspectives"],"prefix":"10.1177","volume":"108","author":[{"given":"Yue","family":"Gao","sequence":"first","affiliation":[{"name":"Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingbing","family":"Cao","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangli","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR), State Key Laboratory of Trauma and Chemical Poisoning, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"He","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6245-0295","authenticated-orcid":false,"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30025"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.05.024"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnab035"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.311227"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.032235"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.04.017"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(19)30255-4"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67394-1"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050461"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2022.05.068"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2023.104513"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.116.003497"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s41073-019-0064-8"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108480"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurjpc\/zwae009"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.34461"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/jhh.2017.56"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2007.04.004"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.764038"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-023-2688-8"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.3233\/CH-242172"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.5551\/jat.55400"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.83914"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.320056"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1063\/5.0167440"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46336-2"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13900"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-022-01519-3"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2023.06.005"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2025.112701"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22084114"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26031003"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2022.01.015"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.1982304"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.652963"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20425-x"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvw053"},{"key":"e_1_3_3_39_2","article-title":"Association of serum PCSK9 levels with platelet function in patients with acute coronary syndromes","volume":"102","author":"Wang W","year":"2023","unstructured":"Wang W, Luo R, Pei D, et al. Association of serum PCSK9 levels with platelet function in patients with acute coronary syndromes. Medicine (Baltimore) 2023; 102: e33026.","journal-title":"Medicine (Baltimore)"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40256-024-00719-4"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046290"},{"key":"e_1_3_3_42_2","article-title":"PCSK9 promotes cardiovascular diseases: recent evidence about its association with platelet activation-induced myocardial infarction","volume":"12","author":"Puteri MU","year":"2022","unstructured":"Puteri MU, Azmi NU, Kato M, et al. PCSK9 promotes cardiovascular diseases: recent evidence about its association with platelet activation-induced myocardial infarction. Life (Basel) 2022; 12: 190.","journal-title":"Life (Basel)"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1615664"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801174"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1177\/1358863X231169324"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/ehjcvp\/pvz022"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01690-3"},{"key":"e_1_3_3_48_2","first-page":"4509","article-title":"Exploring the pleiotropy of PCSK9: a wide range of influences from lipid regulation to extrahepatic function","volume":"18","author":"Wang H","year":"2025","unstructured":"Wang H, Tang G, Wu J, et al. Exploring the pleiotropy of PCSK9: a wide range of influences from lipid regulation to extrahepatic function. J Inflamm Res 2025; 18: 4509\u20134532.","journal-title":"J Inflamm Res"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx002"}],"container-title":["Science Progress"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/00368504251370679","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/00368504251370679","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/00368504251370679","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T11:17:33Z","timestamp":1777634253000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/00368504251370679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1177\/00368504251370679"],"URL":"https:\/\/doi.org\/10.1177\/00368504251370679","relation":{},"ISSN":["0036-8504","2047-7163"],"issn-type":[{"value":"0036-8504","type":"print"},{"value":"2047-7163","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]},"article-number":"00368504251370679"}}