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This ATP\u2010binding cassette (ABC) transporter is responsible for the secretion of phosphatidylcholine into bile canaliculi. Missense genetic variations of ABCB4 are correlated with several rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). In a repurposing strategy to correct intracellularly retained ABCB4 variants, we tested 16 compounds previously validated as cystic fibrosis transmembrane conductance regulator (CFTR) correctors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The maturation, intracellular localization and activity of intracellularly retained ABCB4 variants were analyzed in cell models after treatment with CFTR correctors. In addition, in silico molecular docking calculations were performed to test the potential interaction of CFTR correctors with ABCB4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that the correctors C10, C13, and C17, as well as the combinations of C3\u00a0+\u00a0C18 and C4\u00a0+\u00a0C18, allowed the rescue of maturation and canalicular localization of four distinct traffic\u2010defective ABCB4 variants. However, such treatments did not permit a rescue of the phosphatidylcholine secretion activity of these defective variants and were also inhibitory of the activity of wild type ABCB4. In silico molecular docking analyses suggest that these CFTR correctors might directly interact with transmembrane domains and\/or ATP\u2010binding sites of the transporter.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results illustrate the uncoupling between the traffic and the activity of ABCB4 because the same molecules can rescue the traffic of defective variants while they inhibit the secretion activity of the transporter. We expect that this study will help to design new pharmacological tools with potential clinical interest.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14839","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T04:21:59Z","timestamp":1614658919000},"page":"1344-1357","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Effect of CFTR correctors on the traffic and the function of intracellularly retained ABCB4 variants"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2105-1491","authenticated-orcid":false,"given":"Amel","family":"Ben Saad","sequence":"first","affiliation":[{"name":"Inserm Universit\u00e9 Paris\u2010Saclay Physiopathog\u00e9n\u00e8se et traitement des maladies du foie UMR_S 1193 Orsay France"},{"name":"Inserm Sorbonne Universit\u00e9 Centre de Recherche Saint\u2010Antoine (CRSA) UMR_S 938 Institute of Cardiometabolism and Nutrition (ICAN) Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0736-614X","authenticated-orcid":false,"given":"Virginie","family":"Vauthier","sequence":"additional","affiliation":[{"name":"Inserm Sorbonne Universit\u00e9 Centre de Recherche Saint\u2010Antoine (CRSA) UMR_S 938 Institute of Cardiometabolism and Nutrition (ICAN) Paris France"},{"name":"Universit\u00e9 de Paris Institut Cochin Inserm U1016 CNRS UMR 8104 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1376-5291","authenticated-orcid":false,"given":"\u00c1gota","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Inserm Universit\u00e9 de Limoges UMR 1248 IPPRITT Limoges France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2159-8729","authenticated-orcid":false,"given":"Angelika","family":"Janaszkiewicz","sequence":"additional","affiliation":[{"name":"Inserm Universit\u00e9 de Limoges UMR 1248 IPPRITT Limoges France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Marie","family":"Durand\u2010Schneider","sequence":"additional","affiliation":[{"name":"Inserm Sorbonne Universit\u00e9 Centre de Recherche Saint\u2010Antoine (CRSA) UMR_S 938 Institute of Cardiometabolism and Nutrition (ICAN) Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5740-2372","authenticated-orcid":false,"given":"Alix","family":"Bruneau","sequence":"additional","affiliation":[{"name":"Inserm Sorbonne Universit\u00e9 Centre de Recherche Saint\u2010Antoine (CRSA) UMR_S 938 Institute of Cardiometabolism and Nutrition (ICAN) Paris France"},{"name":"Department of Hepatology &amp; 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