{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:45:26Z","timestamp":1790963126757,"version":"4.1.0"},"reference-count":27,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cassandra contre les Leuc\u00e9mies et Cancers P\u00e9diatriques","award":["OPE-2018-0144"],"award-info":[{"award-number":["OPE-2018-0144"]}]},{"name":"Cassandra contre les Leuc\u00e9mies et Cancers P\u00e9diatriques","award":["RE-2021-1AD-F"],"award-info":[{"award-number":["RE-2021-1AD-F"]}]},{"name":"R\u00e9coltes de l\u2019Espoir","award":["OPE-2018-0144"],"award-info":[{"award-number":["OPE-2018-0144"]}]},{"name":"R\u00e9coltes de l\u2019Espoir","award":["RE-2021-1AD-F"],"award-info":[{"award-number":["RE-2021-1AD-F"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Deregulated lipid metabolism is a common feature of liver cancers needed to sustain tumor cell growth and survival. We aim at taking advantage of this vulnerability and rewiring the oncogenic metabolic hub by targeting the key metabolic player pro-protein convertase subtilisin\/kexin type 9 (PCSK9). We assessed the effect of PCSK9 inhibition using the three hepatoma cell lines Huh6, Huh7 and HepG2 and validated the results using the zebrafish in vivo model. PCSK9 deficiency led to strong inhibition of cell proliferation in all cell lines. At the lipid metabolic level, PCSK9 inhibition was translated by an increase in intracellular neutral lipids, phospholipids and polyunsaturated fatty acids as well as a higher accumulation of lipid hydroperoxide. Molecular signaling analysis involved the disruption of the sequestome 1\/Kelch-like ECH-associated protein 1\/nuclear factor erythroid 2-related factor 2 (p62\/Keap1\/Nrf2) antioxidative axis, leading to ferroptosis, for which morphological features were confirmed by electron and confocal microscopies. The anti-tumoral effects of PCSK9 deficiency were validated using xenograft experiments in zebrafish. The inhibition of PCSK9 was effective in disrupting the oncometabolic process, inducing metabolic exhaustion and enhancing the vulnerability of cancer cells to iron-triggered lipid peroxidation. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat liver cancers.<\/jats:p>","DOI":"10.3390\/cells12010062","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T07:02:12Z","timestamp":1672124532000},"page":"62","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis"],"prefix":"10.3390","volume":"12","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, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"Fatrouni","sequence":"additional","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), Inserm U1312, University of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2487-7571","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Tr\u00e9z\u00e9guet","sequence":"additional","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), Inserm U1312, University of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Dittrich-Domergue","sequence":"additional","affiliation":[{"name":"Laboratoire de Biogen\u00e8se Membranaire, CNRS, UMR 5200, University of Bordeaux, 33140 Villenave d\u2019Ornon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9318-3464","authenticated-orcid":false,"given":"Patrick","family":"Moreau","sequence":"additional","affiliation":[{"name":"Laboratoire de Biogen\u00e8se Membranaire, CNRS, UMR 5200, University of Bordeaux, 33140 Villenave d\u2019Ornon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-5206","authenticated-orcid":false,"given":"G\u00e9raldine","family":"Siegfried","sequence":"additional","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), Inserm U1312, University of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Liet","sequence":"additional","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), Inserm U1312, University of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6957-0384","authenticated-orcid":false,"given":"Abdel-Majid","family":"Khatib","sequence":"additional","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), Inserm U1312, University of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0479-6291","authenticated-orcid":false,"given":"Christophe F.","family":"Grosset","sequence":"additional","affiliation":[{"name":"Bordeaux Institute of Oncology (BRIC), Inserm U1312, University of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassam","family":"Badran","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Beirut 90656, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3465-4630","authenticated-orcid":false,"given":"Hussein","family":"Fayyad-Kazan","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Beirut 90656, Lebanon"}],"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, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3951","DOI":"10.1021\/acs.biochem.0c00477","article-title":"Targeting Lipid Metabolism in Liver Cancer","volume":"59","author":"Alannan","year":"2020","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1038\/sj.bjc.6605007","article-title":"De Novo Fatty-Acid Synthesis and Related Pathways as Molecular Targets for Cancer Therapy","volume":"100","author":"Mashima","year":"2009","journal-title":"Br. 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