{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T12:06:06Z","timestamp":1789214766015,"version":"build-2803163510"},"reference-count":82,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R56HD111119 KM ZK"],"award-info":[{"award-number":["R56HD111119 KM ZK"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Smith\u2013Lemli\u2013Opitz syndrome (SLOS) is a developmental disability arising from bi-allelic pathogenic variants in the 7-dehydrocholestrol reductase (DHCR7) enzyme and the accumulation of 7-dehydrocholesterol (7-DHC). 7-DHC spontaneously oxidizes and gives rise to cytotoxic oxysterols. Our recent high-throughput screening on Dhcr7-deficient Neuro2a cells identified hydroxyzine (HYZ) as a medication that could counteract the high levels of 7-DHC. We assessed the effects of HYZ in Dhcr7-deficient Neuro2a cells, neuronal cultures and glial cultures from Dhcr7T93M\/T93M transgenic mice, and human dermal fibroblasts from patients with SLOS. LC-MS\/MS biochemical analyses revealed a strong modulatory effect of HYZ on post-lanosterol biosynthesis across all four SLOS models. However, the HYZ-induced biochemical changes were complex, dose-dependent, and variable across the four SLOS models. Dhcr7-deficient Neuro2a cells showed decreased 7-DHC, 8-dehydrocholesterol (8-DHC), and desmosterol (DES) levels (all p &lt; 0.01), while neuronal and glial cultures from Dhcr7T93M\/T93M transgenic mice reported 8 significantly altered analytes (all p &lt; 0.001). Human dermal fibroblast from patients with SLOS reacted to HYZ exposure with significantly decreased 7-DHC, 7-dehydrodesmosterol (7-DHD), and dihydrolanosterol (DHL) levels (p &lt; 0.001), coupled with elevation in zymosterol (ZYM), zymostenol (ZYME), and 8-DHC (p &lt; 0.001). Further evaluations are required to determine if the potentially beneficial effects of decreased 7-DHC, 7-DHD and DHL levels in SLOS models and patient biomaterials are counteracted by the rise in other post-lanosterol intermediates.<\/jats:p>","DOI":"10.3390\/biom15040562","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T10:47:41Z","timestamp":1744282061000},"page":"562","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hydroxyzine Effects on Post-Lanosterol Biosynthesis in Smith\u2013Lemli\u2013Opitz Syndrome (SLOS) Models"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8690-4507","authenticated-orcid":false,"given":"Zeljka","family":"Korade","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Child Health Research Institute, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3511-939X","authenticated-orcid":false,"given":"Allison C.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Child Health Research Institute, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7842-4781","authenticated-orcid":false,"given":"Marta","family":"Balog","sequence":"additional","affiliation":[{"name":"Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Child Health Research Institute, Omaha, NE 68198, USA"},{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7331-2601","authenticated-orcid":false,"given":"Keri A.","family":"Tallman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt Institute of Chemical Biology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ned A.","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt Institute of Chemical Biology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5521-0254","authenticated-orcid":false,"given":"Karoly","family":"Mirnics","sequence":"additional","affiliation":[{"name":"Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Child Health Research Institute, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1006\/mgme.2000.3069","article-title":"RSH\/Smith-Lemli-Opitz syndrome: A multiple congenital anomaly\/mental retardation syndrome due to an inborn error of cholesterol biosynthesis","volume":"71","author":"Porter","year":"2000","journal-title":"Mol. 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