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Technopole","award":["CUP:F83B22000040006"],"award-info":[{"award-number":["CUP:F83B22000040006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Defects in lysosomal cholesterol handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann\u2013Pick type C disease (NPCD), where cholesterol export from the endosomal\u2013lysosomal system is impaired due to variants of either NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2). Therapeutic options for NPCD are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as new drug targets for NPCD using patient-derived skin fibroblasts. Treatment with JQ1, a prototype BET protein inhibitor, raised the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose-, time-, and patient-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by pharmacologic inhibition of NPC1 and of histone deacetylase (HDAC) activity, respectively. Taken together, bromodomain proteins should be further explored as therapeutic drug targets for lysosomal diseases like NPCD, and as new components regulating lysosomal function and cholesterol metabolism.<\/jats:p>","DOI":"10.3390\/ijms26125769","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T14:03:11Z","timestamp":1750082591000},"page":"5769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploration of Bromodomain Proteins as Drug Targets for Niemann\u2013Pick Type C Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9135-567X","authenticated-orcid":false,"given":"Martina","family":"Parente","sequence":"first","affiliation":[{"name":"Department of Science, Section Biomedical Science and Technology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lie","family":"Barthelemy","sequence":"additional","affiliation":[{"name":"Institut des Neurosciences Cellulaires et Int\u00e9gratives, Centre National de la Recherche Scientifique, Universit\u00e9 de Strasbourg, 8 All\u00e9e du G\u00e9n\u00e9ral Rouvillois, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9979-1142","authenticated-orcid":false,"given":"Claudia","family":"Tonini","sequence":"additional","affiliation":[{"name":"Department of Science, Section Biomedical Science and Technology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9939-3767","authenticated-orcid":false,"given":"Sara","family":"Caputo","sequence":"additional","affiliation":[{"name":"Department of Science, Section Biomedical Science and Technology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Sacchi","sequence":"additional","affiliation":[{"name":"Department of Science, Section Biomedical Science and Technology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6339-6397","authenticated-orcid":false,"given":"Stefano","family":"Leone","sequence":"additional","affiliation":[{"name":"Department of Science, Section Biomedical Science and Technology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0465-9470","authenticated-orcid":false,"given":"Marco","family":"Segatto","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone s.n.c., 86090 Pesche, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7085-1431","authenticated-orcid":false,"given":"Frank W.","family":"Pfrieger","sequence":"additional","affiliation":[{"name":"Institut des Neurosciences Cellulaires et Int\u00e9gratives, Centre National de la Recherche Scientifique, Universit\u00e9 de Strasbourg, 8 All\u00e9e du G\u00e9n\u00e9ral Rouvillois, 67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2511-6168","authenticated-orcid":false,"given":"Valentina","family":"Pallottini","sequence":"additional","affiliation":[{"name":"Department of Science, Section Biomedical Science and Technology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy"},{"name":"Neuroendocrinology Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Via del Fosso Fiorano 64, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.chembiol.2025.02.003","article-title":"Mechanisms and functions of lysosomal lipid homeostasis","volume":"32","author":"Ebner","year":"2025","journal-title":"Cell Chem. 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USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/ncomms1735","article-title":"Lipid storage disorders block lysosomal trafficking by inhibiting a trp channel and lysosomal calcium release","volume":"3","author":"Shen","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4876","DOI":"10.1093\/hmg\/dds324","article-title":"Impaired proteolysis underlies autophagic dysfunction in niemann-pick type c disease","volume":"21","author":"Elrick","year":"2012","journal-title":"Hum. Mol. 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