{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T12:47:01Z","timestamp":1782478021885,"version":"3.54.5"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["IUBMB Life"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Proprotein convertase subtilisin\/kexin type 9 (PCSK9) acts as a pleiotropic modulator of inflammation. This study aimed to investigate the role and underlying mechanism of PCSK9 in Kawasaki disease (KD)\u2010associated vasculitis. A\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Candida albicans<\/jats:italic>\n                    <\/jats:styled-content>\n                    water\u2010soluble fraction (CAWS)\u2010induced murine vasculitis model (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20095\u20138 mice per group) and CAWS\u2010stimulated RAW 264.7 macrophages (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20093\u20138 independent experiments) were used. PCSK9 was pharmacologically inhibited in\u00a0vivo with SBC\u2010115076 and in\u00a0vitro with PF\u201006446846. Vascular pathology, inflammatory markers, macrophage polarization, and signaling pathways were evaluated using hematoxylin\u2013eosin (H&amp;E) staining, immunofluorescence (IF), Western blot, quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR), and RNA sequencing (RNA\u2010seq). CAP1 overexpression was performed via lentiviral infection in RAW 264.7 cells to further validate its functional role. PCSK9 expression was significantly upregulated (two\u2010fold) in the coronary arteries of CAWS\u2010treated mice, and PCSK9 was predominantly co\u2010localized with macrophages. Pharmacological inhibition of PCSK9 attenuated coronary arteritis, reduced the inflammatory infiltrate fraction by 54%, attenuated systemic inflammation, and decreased cardiac macrophage infiltration by 89%. In\u00a0vitro, PCSK9 blockade suppressed CAWS\u2010induced M1 macrophage polarization, as shown by reduced expression of the markers CD86 (by 96%) and iNOS (by 60%), and decreased secretion of the pro\u2010inflammatory cytokines TNF\u2010\u03b1 (by 80%), IL\u20101\u03b2 (by 86%), and IL\u20106 (by 89%). Transcriptomic analysis identified the NF\u2010\u03baB pathway as a key downstream signaling pathway. Mechanistically, PCSK9 inhibition downregulated CAP1 (adenylyl cyclase\u2010associated protein 1) expression by 64% and suppressed NF\u2010\u03baB p65 nuclear translocation by 91% in macrophages. Importantly, CAP1 overexpression reversed the inhibitory effects of PCSK9 blockade on p65 nuclear translocation, M1 polarization, and inflammatory cytokine production. PCSK9 promotes KD\u2010like vasculitis by activating the CAP1\u2010mediated NF\u2010\u03baB pathway in macrophages, thereby driving pro\u2010inflammatory responses. Pharmacological inhibition of PCSK9 attenuates vascular immunopathology, highlighting PCSK9 as a potential therapeutic target for KD.\n                  <\/jats:p>","DOI":"10.1002\/iub.70119","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:18:49Z","timestamp":1781227129000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism of\n                    <scp>PCSK9<\/scp>\n                    \u2010Mediated Macrophage Activation via the\n                    <scp>CAP1<\/scp>\n                    \/\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    Pathway in\n                    <scp>CAWS<\/scp>\n                    \u2010Induced Kawasaki Disease Vasculitis"],"prefix":"10.1002","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9202-7962","authenticated-orcid":false,"given":"Hao","family":"Zhang","sequence":"first","affiliation":[{"name":"Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dujuan","family":"Shuai","sequence":"additional","affiliation":[{"name":"Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaohua","family":"Ruan","sequence":"additional","affiliation":[{"name":"Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Wu","sequence":"additional","affiliation":[{"name":"Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Wang","sequence":"additional","affiliation":[{"name":"Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9929-0674","authenticated-orcid":false,"given":"Maoping","family":"Chu","sequence":"additional","affiliation":[{"name":"Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8292-5362","authenticated-orcid":false,"given":"Xing","family":"Rong","sequence":"additional","affiliation":[{"name":"Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.2188\/jea.JE20190065"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2020.05.034"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2014-307536"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.21542\/gcsp.2017.20"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801593"},{"issue":"5","key":"e_1_2_11_7_1","first-page":"E181","article-title":"Diagnosis, Treatment, and Long\u2010Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association","volume":"140","author":"McCrindle B. 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