gene

CYP46A1

Entity Detail — Knowledge Graph Node

Understanding Entity Pages

This page aggregates everything SciDEX knows about CYP46A1: its mechanistic relationships (Knowledge Graph edges), hypotheses targeting it, analyses mentioning it, and supporting scientific papers. The interactive graph below shows its immediate neighbors. All content is AI-synthesized from peer-reviewed literature.

935Connections

4Hypotheses

2Analyses

50Outgoing

50Incoming

2Experiments

2Debates

Summary

Cholesterol 24-hydroxylase (CYP46A1) is the rate-limiting enzyme for brain cholesterol turnover, converting cholesterol to 24S-hydroxycholesterol. Enhances cholesterol efflux and modulates synaptic plasticity. Gene therapy and pharmacological upregulation improve cognition in AD models by reducing amyloid burden.

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🧬 Gene Info

Gene Symbol	CYP46A1
Full Name	Cholesterol 24-Hydroxylase
Aliases	CH24H
Chromosome	14
Protein Type	Enzyme
Target Class	Enzyme
Function	CYP46A1 plays a critical role in cholesterol metabolism, which is intimately connected to Alzheimer's disease pathogenesis through multiple mechanisms:
Mechanism of Action	Small molecule activator of cholesterol 24-hydroxylase enhancing brain cholesterol turnover
Primary Expression	neurons of the brain that catalyzes the conversion of cholesterol to 24-hydroxycholesterol
Druggability	Medium (0.51)
Clinical Stage	Approved
Pathways	Cholesterol metabolism, Oxysterol synthesis, BBB transport
UniProt ID	G3V366
Ensembl ID	ENSG00000146386
GeneCards	CYP46A1
Human Protein Atlas	CYP46A1
Associated Diseases	Als, Alzheimer, Alzheimer's disease, Amyotrophic Lateral Sclerosis
Known Drugs/Compounds	efavirenz, EFAVIRENZ, efavirenz metabolites, lycibarbarspermidines D, neurotransmitters, spermidine
Interactions	ABCA1, abca2, ABCA2, AD, ADAM10, ALZHEIMER
SciDEX Target	View Target Profile (6 clinical trials)
SciDEX Hypotheses	CYP46A1 Gene Therapy for Age-Related TREM2-Mediate CYP46A1 Overexpression Gene Therapy TREM2-Mediated Cholesterol Dysregulation in Microg (+1 more)
KG Connections	935 knowledge graph edges
Databases	GeneCards NCBI Gene HPA STRING

🧬 3D Structure Comparison — CYP46A1 Experimental (PDB) vs Predicted (AlphaFold) — click to expand

📄 Experimental Structure

2Q9F — X-ray / Cryo-EM

🔮 AI Predicted Structure

G3V366 — AlphaFold

Left: Experimental structure from RCSB PDB | Right: AI-predicted structure from AlphaFold | Powered by Mol*

Wiki Pages (1)

Knowledge base pages for this entity

Canonical Page

CYP46A1 — Cholesterol 24-Hydroxylase

gene · 613 words

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Pathway Diagram

graph TD
    CYP46A1["CYP46A1 Enzyme"] -->|"Hydroxylates"| Chol["Cholesterol"]
    Chol -->|"Converts to"| 24HC["24-Hydroxycholesterol"]
    24HC -->|"Crosses"| BBB["Blood-Brain Barrier"]
    24HC -->|"Exits to"| Blood["Bloodstream"]
    CYP46A1 -->|"Regulates"| Homeostasis["Brain Cholesterol Homeostasis"]
    Dysregulation -.Causes.-> Excess["Cholesterol Excess"]
    Excess -.Associated with.-> AD["Alzheimer's Disease"]
    CYP46A1 -.Upregulation therapeutic.-> Clearance["Enhanced Clearance"]

Outgoing (620)

Target	Relation	Type	Str
Cholesterol Homeostasis	regulates	process	0.95
Cholesterol Accumulation	downregulates	phenotype	0.95
Brain Cholesterol Accumulation	inhibits	phenotype	0.95
GLIOBLASTOMA	downregulates	disease	0.90
lipid metabolism	participates_in	pathway	0.90
neurons	expressed_in	cell_type	0.90
Alzheimer'S Disease	risk_factor_for	disease	0.90
brain diseases	benefits_for	disease	0.90
NEURON	expressed_in	cell_type	0.85
Alzheimer's disease	increases_risk	disease	0.80
Amyloid-β	regulates	protein	0.80
APOE ε4 allele	interacts_with	gene	0.80
APOE4	interacts_with	protein	0.80
cell proliferation	inhibits	process	0.80
Niemann-Pick type C disease	implicated_in	disease	0.80
Alzheimer's disease	biomarker_for	disease	0.80
Alzheimer's disease	treats	disease	0.80
Alzheimer's disease	regulates	disease	0.80
neurons	associated_with	cell_type	0.80
GLAUCOMA	implicated_in	disease	0.80
neurons	activates	cell_type	0.80
oxidative stress response	participates_in	pathway	0.80
TLR4	activates	gene	0.70
DOPAMINERGIC	inhibits	cell_type	0.70
TNF	activates	gene	0.70
NRF2	expresses	gene	0.70
KEAP1	expresses	gene	0.70
NRF2	activates	gene	0.70
KEAP1	activates	gene	0.70
HO1	expresses	gene	0.70
STING	associated_with	gene	0.70
neurons	treats	cell_type	0.70
neurons	inhibits	cell_type	0.70
Alzheimer's disease	inhibits	disease	0.70
blood-brain barrier	expressed_in	brain_region	0.70
Huntington's disease	treats	disease	0.70
WHITE MATTER	activates	brain_region	0.70
blood-brain barrier	participates_in	pathway	0.70
COGNITIVE DECLINE	protects_against	phenotype	0.70
AMYLOID	protects_against	protein	0.70
HIPPOCAMPUS	exacerbates	brain_region	0.70
NRF2 PATHWAY	regulates	pathway	0.70
COGNITIVE DECLINE	exacerbates	phenotype	0.70
NEURONS	exacerbates	cell_type	0.70
NRF2 PATHWAY	inhibits	pathway	0.70
HIPPOCAMPUS	causes	brain_region	0.70
NEUROINFLAMMATION	inhibits	phenotype	0.70
Huntington's disease	implicated_in	disease	0.70
DEPRESSION	implicated_in	disease	0.70
EPILEPSY	implicated_in	disease	0.70

Incoming (315)

Source	Relation	Type	Str
h-var-1dc420e7d8	targets_gene	hypothesis	0.90
h-2600483e	targets_gene	hypothesis	0.90
h-var-e0e82ff2e2	targets_gene	hypothesis	0.90
h-var-3fbcfc0e6c	targets_gene	hypothesis	0.90
lycibarbarspermidines D	inhibits	compound	0.90
ATAD3A	inhibits	gene	0.90
efavirenz metabolites	activates	compound	0.80
APOE	co_mentioned_with	gene	0.80
h-2600483e	targets	hypothesis	0.80
ASTROCYTE	targets	cell_type	0.70
ASTROCYTE	expresses	cell_type	0.70
ABCA1	expresses	gene	0.70
APOE	expresses	gene	0.70
APP	transports	gene	0.70
SYNAPTIC PLASTICITY	inhibits	phenotype	0.70
SYNAPTIC PLASTICITY	stabilizes	phenotype	0.70
ABCA1	co_mentioned_with	gene	0.70
SYNAPTIC PLASTICITY	protects_against	phenotype	0.70
SYNAPTIC PLASTICITY	treats	phenotype	0.70
ADAM10	inhibits	gene	0.70
neurotransmitters	activates	compound	0.70
STROKE	targets	disease	0.65
NEURON	targets	cell_type	0.65
ABCA1	regulates	gene	0.65
APOE	regulates	gene	0.65
CHOLESTEROL	encodes	phenotype	0.65
TNF	inhibits	gene	0.65
TNF	regulates	gene	0.65
ABCA1	associated_with	gene	0.65
ASTROCYTE	associated_with	gene	0.65
AUTOPHAGY	associated_with	gene	0.65
BACE1	associated_with	gene	0.65
SPHINGOMYELIN	activates	phenotype	0.65
SPHINGOMYELIN	regulates	phenotype	0.65
APP	associated_with	gene	0.65
ALS	associated_with	gene	0.65
ALZHEIMER	expressed_in	disease	0.65
ALZHEIMER	associated_with	gene	0.65
CD33	associated_with	gene	0.65
AMYLOID	associated_with	gene	0.65
ATP	regulates	gene	0.65
CX3CR1	associated_with	gene	0.65
BACE1	inhibits	gene	0.60
GSK3B	inhibits	gene	0.60
TAU	therapeutic_target	gene	0.60
TREM2	inhibits	gene	0.60
HMGCR	associated_with	gene	0.60
CYP7B1	inhibits	gene	0.60
TNF	therapeutic_target	gene	0.60
APOE	synergizes_with	gene	0.60

Targeting Hypotheses (4)

Hypotheses where this entity is a therapeutic target

Hypothesis	Score	Disease	Analysis
CYP46A1 Gene Therapy for Age-Related TREM2-Mediated Microgli	0.921	neurodegeneration	Lipid raft composition changes in synapt
CYP46A1 Overexpression Gene Therapy	0.919	neurodegeneration	Lipid raft composition changes in synapt
TREM2-Mediated Cholesterol Dysregulation in Microglial Senes	0.869	neurodegeneration	Gene expression changes in aging mouse b
CYP46A1 Suppression for Tau-Mediated Neurodegeneration	0.792	neurodegeneration	Lipid raft composition changes in synapt

Mentioning Analyses (2)

Scientific analyses that reference this entity

SEA-AD Gene Expression Profiling — Allen Brain Cell Atlas

neurodegeneration | 2026-04-02 | 5 hypotheses Top: 0.761

Lipid raft composition changes in synaptic neurodegeneration

neurodegeneration | 2026-04-01 | 12 hypotheses Top: 0.921

Experiments (2)

Experimental studies targeting or related to this entity

Experiment	Type	Disease	Score	Feasibility	Model	Status	Est. Cost
Metal Ion Homeostasis Dysregulation in Alzheimer's Disease	validation	Alzheimer's Disease	0.400	0.50	human	proposed	$2,730,000
Wilson Disease Neurodegeneration: Mechanism and Therapeutic Response	clinical	Neurodegeneration	0.400	0.50	human	proposed	$7,500,000

Related Papers (20)

Scientific publications cited in analyses involving this entity

Title & PMID	Authors	Journal	Year	Citations
Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1. [PMID:37384704]	Zhang T, Xu D, Trefts E, Lv M, Inuzuka H	Science	2023	1
TREM2, microglia, and Alzheimer's disease. [PMID:33516818]	Qin Q, Teng Z, Liu C, Li Q, Yin Y, Tang	Mech Ageing Dev	2021	1
Complement and microglia mediate early synapse loss in Alzheimer mouse models. [PMID:27033548]	Hong S, Beja-Glasser VF, Nfonoyim BM, Fr	Science	2016	1
Potential Biological Processes Related to Brain SLC13A5 Across the Lifespan: Wei [PMID:41750164]	Ferreira BK, Schuck PF, Ferreira GC, Fre	Brain sciences	2026	0
How cytochrome P450 enzymes in humans are involved in Parkinson's disease: a lit [PMID:41730497]	Ren B, Yan H, Han C, Sun S, Wang D, Xu Y	Neuroscience	2026	0
Dysregulated Cholesterol Clearance via CYP46A1 Contributes to Cerebellar Sterol [PMID:41828569]	Tapia PJ, Rivera BI, Espinoza CS, Stolze	International journal of molec	2026	0
Efavirenz treatment improves retinal vaso-obliteration and pathological neovascu [PMID:41810243]	Bailey B, Rudd Zhong Manis J, Seth G, Ra	Frontiers in medicine	2026	0
Radiosynthesis and Evaluation of 18F‑Labeled Deuterated Radioligand for Positron [PMID:41704371]	Li Y, Song Z, Shi H, Zhao T, Chen J, Zho	ACS medicinal chemistry letter	2026	0
Streptozotocin and L-Buthionine-Sulfoximine Decrease Neuron Membrane Lipid Packi [PMID:40439741]	Martins YA, Cardinali CAEF, Costa AP, To	Neurotoxicity research	2025	0
Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model b [PMID:40540390]	["Ali T", "Cashion J", "Hannaoui S", "Ah	JCI insight	2025	0
The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkins [PMID:39964974]	Dai L, Wang J, Meng L, Zhang X, Xiao T,	PLoS biology	2025	0
Sterol imbalances and cholesterol-24-hydroxylase dysregulation is linked to the [PMID:40045480]	Griffiths L, Hawkins K, Yutuc E, Angelin	Brain pathology (Zurich, Switz	2025	0
Astrocyte-neuron combined targeting for CYP46A1 gene therapy in Huntington's dis [PMID:40859407]	Parsai LH, Chali F, Subashi E, Zeitouny	Acta neuropathologica communic	2025	0
Overexpression of cholesterol 24-hydroxylase CYP46A1 attenuates retinal dysfunct [PMID:40975483]	Long Z, Zhang J, Feng J, He T	Experimental eye research	2025	0
Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinfl [PMID:40987840]	Zhao Q, Li J, Feng J, Wang X, Liu Y, Wan	Nature metabolism	2025	0
Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperp [PMID:40653030]	Giannelli S, Eroli F, Loera-Valencia R,	Neurobiology of disease	2025	0
Mesenchymal stem cells overexpressing CYP46A1 inhibit lipopolysaccharide-induced [PMID:40609611]	Shao Y, Ma B, Jin R, Kong N, Tang J, Li	European journal of pharmacolo	2025	0
ABC Transporters, APOE, CYP46A1, and LRP1 Gene Polymorphisms as Markers of Demen [PMID:41226793]	Machowska M, Leszek J, Rączy-Krzemianows	International journal of molec	2025	0
Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hall [PMID:38142760]	Nunes MJ, Carvalho AN, Reis J, Costa D,	Biochimica et biophysica acta.	2024	0
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition [PMID:38266095]	Latorre-Leal M, Rodriguez-Rodriguez P, F	Science advances	2024	0

Debates (2)

Multi-agent debates referencing this entity

Investigate how lipid raft composition (cholesterol metabolism, sphingolipids) c

closed · Rounds: 5 · Score: 0.93 · 2026-04-11

Cell-type specific expression patterns of neurodegeneration genes in SEA-AD

closed · Rounds: 3 · Score: 0.68 · 2026-04-02