{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CYP46A1, also known as cholesterol 24‐hydroxylase, is a brain‐specific enzyme that converts cholesterol into 24S‐hydroxycholesterol, the principal metabolite that enables cholesterol removal from the central nervous system (1,3). This conversion is central to maintaining cholesterol homeostasis and modulating synaptic function and neuronal signaling. Dysregulation of CYP46A1 has been implicated in several neurodegenerative conditions. For example, in Huntington’s disease, reduced CYP46A1 levels in the striatum are associated with neuronal loss and motor deficits, whereas restoration of its activity protects vulnerable neurons and alleviates disease phenotypes (2). In Alzheimer’s disease models, pharmacological activation of CYP46A1—using agents such as efavirenz—enhances cerebral cholesterol turnover, reduces amyloid burden and neuroinflammation, and ultimately improves cognitive performance (4). Similarly, in glioblastoma, decreased CYP46A1 expression disrupts cholesterol metabolism in tumor cells, and its ectopic re‐expression can suppress proliferation and tumor growth (5). Beyond its homeostatic role, the 24S‐hydroxycholesterol produced by CYP46A1 functions as a bioactive ligand for nuclear receptors such as RORα and RORγ, thereby influencing gene transcription and neuronal function (6). Genetic and epigenetic investigations also reveal that variants and regulatory mechanisms affecting CYP46A1 expression may contribute to Alzheimer’s disease risk and progression (7,8,9). Finally, structural studies of CYP46A1 have provided insights into its membrane association and substrate entry pathway, underscoring its specialized function in neurons (10). Collectively, these findings establish CYP46A1 as a pivotal mediator of brain cholesterol turnover with emerging therapeutic potential in neurodegenerative and proliferative brain disorders."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andreas Papassotiropoulos, Johannes R Streffer, Magdalini Tsolaki, et al. 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