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The atypical enzyme, proprotein convertase subtilisin\/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver.<\/jats:p>","DOI":"10.3390\/cells11244132","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T07:27:30Z","timestamp":1671434850000},"page":"4132","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0640-5055","authenticated-orcid":false,"given":"Malak","family":"Alannan","sequence":"first","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6503-9342","authenticated-orcid":false,"given":"Nabil G.","family":"Seidah","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, IRCM, University of Montreal, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4030-4538","authenticated-orcid":false,"given":"Aksam J.","family":"Merched","sequence":"additional","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jacl.2014.02.011","article-title":"The National Lipid Association\u2019s Statin Safety Task Force, null An Assessment by the Statin Liver Safety Task Force: 2014 Update","volume":"8","author":"Bays","year":"2014","journal-title":"J. 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