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Cholesterol homeostasis is essential for normal brain function. CYP46A1, crucial for brain cholesterol turnover and reduced in some neurodegenerative diseases, is a potential neuroprotective target. We hypothesized that CYP46A1 is downregulated in MS brains and linked to cholesterol dysbalance. Mass spectrometric analysis of sterols was performed from matched plasma and cerebrospinal fluid (CSF) in an all\u2010female MS cohort (<jats:italic>n<\/jats:italic>\u2009=\u200932, mean age\u2009=\u200933). Disability status was recorded at baseline and follow\u2010up. MS brain tissue samples (<jats:italic>n<\/jats:italic>\u2009=\u200911; 7 females; ages 38\u201367; 10 Secondary Progressive MS, 1 Primary Progressive MS; Disease Duration: 13\u201349\u2009years) and control samples (<jats:italic>n<\/jats:italic>\u2009=\u20098; 3 females; ages 41\u201368) analysed for pathological regions using mass spectrometry and RNA expression using in\u2010situ hybridization. Significant dysregulation in 25\u2010hydroxycholesterol, 27\u2010hydroxycholesterol and 3\u03b2\u2010hydroxycholestenoic acid in CSF correlated with disability at baseline and follow\u2010up in the patient population. In brain tissue, reduced cholesterol, 24S\u2010hydroxycholesterol and 24S,25\u2010epoxycholesterol were observed in white matter lesions (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), linked to CYP46A1 activity. CYP46A1 expression was enriched in neurons, with reductions in MS grey matter lesions and non\u2010lesions compared to controls (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Cholesterol metabolism is dysregulated in MS and is associated with reduced neuron\u2010specific CYP46A1 expression. Modulating CYP46A1, a druggable target, may benefit progressive MS.<\/jats:p>","DOI":"10.1111\/bpa.70001","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:30:59Z","timestamp":1741739459000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sterol imbalances and cholesterol\u201024\u2010hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8713-3687","authenticated-orcid":false,"given":"Lauren","family":"Griffiths","sequence":"first","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eylan","family":"Yutuc","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Angelini","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Racheal","family":"Fosuah","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Pacciarini","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Dickson","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Robertson","sequence":"additional","affiliation":[{"name":"Division of Psychological Medicine and Clinical Neurosciences, School of Medicine Cardiff University  Cardiff UK"},{"name":"Helen Durham Unit University Hospital of Wales  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Childs","sequence":"additional","affiliation":[{"name":"Division of Psychological Medicine and Clinical Neurosciences, School of Medicine Cardiff University  Cardiff 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UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqin","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-9157","authenticated-orcid":false,"given":"Owain W.","family":"Howell","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences Swansea University  Swansea 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