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Using histomorphology-guided spatial proteomics, here we delineate molecular programs associated with plaque cap phenotype across discrete plaque subregions. In 112 carotid endarterectomy specimens, differences between thin-cap and thick-cap plaques were predominantly localized to the necrotic core and fibrous cap. These differences were enriched for processes related to inflammation, lipid handling, extracellular matrix remodeling and ossification\/calcification, and supported the presence of proteome-based plaque subtypes. PCSK9 was among the proteins most strongly associated with thin-cap plaques. Consistently, an in vitro model of necrotic core-like oxidative and inflammatory stress increased PCSK9 secretion in primary vascular smooth muscle cells. Together, these findings localize molecular programs associated with cap phenotype to plaque compartments and provide a framework for spatially informed biomarker discovery in advanced carotid atherosclerosis.<\/jats:p>","DOI":"10.1038\/s44161-026-00827-1","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T09:06:49Z","timestamp":1782119209000},"page":"605-623","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Proteomics reveals spatial and molecular heterogeneities in advanced atherosclerotic carotid artery plaques"],"prefix":"10.1038","volume":"5","author":[{"given":"Ankit","family":"Sinha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8031-017X","authenticated-orcid":false,"given":"Nadja","family":"Sachs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6187-3660","authenticated-orcid":false,"given":"Elena","family":"Kratz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5984-3529","authenticated-orcid":false,"given":"Jessica","family":"Pauli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-1131","authenticated-orcid":false,"given":"Sophia","family":"Steigerwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1985-7733","authenticated-orcid":false,"given":"Vincent","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry M.","family":"Nordmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enes","family":"Ugur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin H.","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Luise","family":"Engl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8441-6067","authenticated-orcid":false,"given":"Patricia","family":"Skowronek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denys","family":"Oliinyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1043-6591","authenticated-orcid":false,"given":"Andreas","family":"Metousis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7159-8271","authenticated-orcid":false,"given":"Moritz","family":"von Scheidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0356-5571","authenticated-orcid":false,"given":"Michael","family":"Wierer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8110-8627","authenticated-orcid":false,"given":"Hanna","family":"Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6428-3001","authenticated-orcid":false,"given":"Heribert","family":"Schunkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Branzan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5228-2634","authenticated-orcid":false,"given":"Lars","family":"Maegdefessel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1292-4799","authenticated-orcid":false,"given":"Matthias","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"827_CR1","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1056\/NEJMcp1214999","volume":"369","author":"JC Grotta","year":"2013","unstructured":"Grotta, J. 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