{"gene":"DHCR24","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2000,"finding":"Seladin-1/DHCR24 inhibits caspase-3 activation in response to amyloid-beta toxicity and oxidative stress, protecting cells from apoptotic cell death; endogenous seladin-1 is cleaved to a 40 kDa derivative in a caspase-dependent manner during apoptosis.","method":"Functional expression in human neuroglioma H4 cells; caspase-3 activity assays; Western blotting","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional expression with caspase-3 readout, single lab, two orthogonal methods (activity assay + immunoblot)","pmids":["11007892"],"is_preprint":false},{"year":2004,"finding":"Following oncogenic and oxidative stress, Seladin-1/DHCR24 binds the p53 amino terminus and displaces the E3 ubiquitin ligase Mdm2 from p53, causing p53 accumulation. Seladin-1 also associates with Mdm2 independently of p53. Ablation of Seladin-1 bypasses Ras-induced senescence and allows cellular transformation; mutants disrupting association with p53 or Mdm2 lose this tumor-suppressive activity.","method":"Direct genetic screen; co-immunoprecipitation; loss-of-function (siRNA/ablation) in rodent and human fibroblasts; mutagenesis of interaction interfaces; transformation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, epistasis screen, multiple orthogonal methods in a single rigorous study","pmids":["15577914"],"is_preprint":false},{"year":2006,"finding":"Seladin-1/DHCR24 is required for normal cholesterol biosynthesis and the formation of cholesterol-rich detergent-resistant membrane domains (DRMs/lipid rafts) in mouse brain. Seladin-1 deficiency displaces beta-secretase (BACE) from DRMs into APP-containing membrane fractions, increasing beta-cleavage of APP and Aβ levels; overexpression reverses this, inducing plasmin activation and reducing BACE processing.","method":"DHCR24 knockout mouse brain analysis; cholesterol quantification; DRM fractionation; BACE activity assays; Aβ ELISA; seladin-1 overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO and overexpression with multiple orthogonal biochemical readouts (fractionation, enzyme activity, peptide quantification)","pmids":["16407971"],"is_preprint":false},{"year":2006,"finding":"DHCR24 knockout mice die within hours of birth with lethal dermopathy; DHCR24-deficient epidermis lacks cholesterol (replaced by desmosterol) and shows loss of differentiation markers (abnormal keratin 6/14 expression, altered filaggrin/loricrin/involucrin), confirming DHCR24 catalyzes desmosterol→cholesterol conversion essential for epidermal differentiation and barrier function.","method":"Targeted gene disruption (DHCR24−/− mice); sterol quantification; immunohistochemistry for keratin/differentiation markers; trans-epidermal water loss measurement; Lucifer yellow permeability assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with multiple orthogonal biochemical and functional readouts","pmids":["16410790"],"is_preprint":false},{"year":2006,"finding":"DHCR24−/− mouse embryonic fibroblasts (MEFs) undergo apoptosis upon cholesterol depletion (serum withdrawal) due to disruption of caveolae and impaired insulin receptor (IR)–caveolin-1 co-localization, leading to inactivation of the Akt–Bad survival cascade. Cholesterol repletion rescues Akt activation and prevents apoptosis.","method":"DHCR24−/− MEF cultures; subcellular fractionation; immunocytochemistry; phospho-Akt/Bad Western blotting; insulin stimulation rescue experiments","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO cells plus multiple orthogonal mechanistic readouts (fractionation, kinase phosphorylation, rescue experiment)","pmids":["16513830"],"is_preprint":false},{"year":2007,"finding":"DHCR24/seladin-1 overexpression confers resistance to oxidative stress in a cholesterol-dependent manner; mutating the reductase activity abolished this protective effect. Under chronic oxidative stress, low DHCR24 levels reduce p53 stability (via elevated p53 ubiquitination/degradation) independently of cholesterol, and DHCR24 ablation prevents neuronal apoptosis in a p53-dependent manner.","method":"Neuroblastoma SH-SY5Y cell overexpression; reductase-activity mutants; cholesterol quantification; p53 ubiquitination assays; primary neuron knockdown with p53 rescue","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of catalytic residue, enzymatic activity measurement, p53 ubiquitination assay, and primary neuron KD all in one study","pmids":["17984220"],"is_preprint":false},{"year":2008,"finding":"Seladin-1/DHCR24 overexpression increases membrane cholesterol content, reduces accumulation of Aβ42 pre-fibrillar aggregates at the plasma membrane, and prevents amyloid-induced cytosolic Ca2+ rise. Cholesterol depletion (with the specific seladin-1 inhibitor 5,22E-cholestadien-3-ol or methyl-β-cyclodextrin) has the opposite effect.","method":"SH-SY5Y neuroblastoma overexpression; PEG-cholesterol supplementation; seladin-1 inhibitor treatment; confocal microscopy of Aβ membrane accumulation; intracellular Ca2+ imaging","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor plus overexpression, single lab, two orthogonal functional readouts","pmids":["18194465"],"is_preprint":false},{"year":2008,"finding":"Seladin-1/DHCR24 is a fundamental mediator of estrogen (17β-estradiol, raloxifene, tamoxifen)-induced neuroprotection; siRNA silencing of seladin-1 abolishes estrogen protection against Aβ and oxidative stress toxicity and caspase-3 activation. Half-palindromic estrogen-responsive elements in the seladin-1 promoter confer functional estrogen receptor-alpha-mediated transcriptional activation.","method":"siRNA knockdown in fetal neuroepithelial cells; caspase-3 activity assays; luciferase reporter assay with ER-alpha co-transfection; bioinformatic promoter analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with functional caspase readout plus reporter assay validation of ERE, single lab","pmids":["18499757"],"is_preprint":false},{"year":2008,"finding":"Seladin-1/DHCR24 is transcriptionally regulated by liver X receptor (LXR): an LXR response element was identified within the second intron of the DHCR24 gene that confers LXR-specific ligand responsiveness; seladin-1/DHCR24 expression is decreased in skin of LXRβ-null mice.","method":"Whole-genome ChIP for LXRα occupancy; luciferase reporter assays in HepG2 and HEK293 cells; LXRβ-null mouse gene expression","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identification of binding site plus reporter assay and in vivo KO validation, single lab","pmids":["18815215"],"is_preprint":false},{"year":2008,"finding":"Androgen receptor (AR) regulates seladin-1/DHCR24 expression via androgen-responsive element sequences in its promoter; metastatic AR-negative prostate cancer cells have reduced seladin-1/DHCR24 expression and cholesterol; androgen ablation in prostate cancer patients reduces seladin-1/DHCR24 expression.","method":"Promoter sequence analysis; AR-positive vs. AR-negative cell line comparison; patient tissue RT-PCR and androgen-ablation treatment cohort","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter element identification plus cell line and patient tissue expression, but no direct AR binding assay in this paper","pmids":["18762779"],"is_preprint":false},{"year":2009,"finding":"Down-regulation of seladin-1 in SH-SY5Y cells under apoptotic conditions increases caspase-3 activity, which depletes the BACE1-sorting protein GGA3, leading to increased BACE1 protein levels and activity and enhanced amyloidogenic APP processing and Aβ production. These effects are not seen under normal growth conditions.","method":"siRNA knockdown in SH-SY5Y cells; caspase-3 activity assays; GGA3/BACE1 Western blotting; Aβ ELISA; apoptosis induction","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple pathway readouts (caspase-3, GGA3, BACE1, Aβ), single lab, mechanistically ordered epistasis","pmids":["19815556"],"is_preprint":false},{"year":2009,"finding":"ACTH induces nuclear relocalization of seladin-1 in rat adrenal fasciculata cells (from cytoplasm/cis-Golgi to nucleus), which is blocked by the DHCR24 inhibitor U18666A. In human fasciculata cells, seladin-1 is primarily ER-localized. Inhibition of seladin-1 abolishes ACTH-induced DHEA secretion but not cortisol secretion, and reduces ACTH-induced 11β-hydroxylase expression in rats.","method":"Immunofluorescence; subcellular fractionation; U18666A pharmacological inhibition; steroid secretion measurements (ELISA); immunohistochemistry","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation plus pharmacological inhibition with functional steroid secretion readout, single lab","pmids":["19520779"],"is_preprint":false},{"year":2010,"finding":"DHCR24 expression is induced by HCV infection in human hepatocytes; siRNA silencing of DHCR24 decreases HCV replication in replicon lines and HCV JFH-1-infected cells; the DHCR24 inhibitor U18666A suppresses HCV replication in vitro and in humanized chimeric mice, with synergistic effect when combined with interferon.","method":"siRNA knockdown; U18666A pharmacological inhibition; HCV replicon and JFH-1 infection assays; chimeric mouse model with humanized liver","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA KD and pharmacological inhibition in vitro and in vivo, multiple independent readouts, replicated across cell and animal models","pmids":["21184787"],"is_preprint":false},{"year":2011,"finding":"The endogenous oxysterol 24(S),25-epoxycholesterol (24,25EC) rapidly inhibits DHCR24 enzyme activity (not protein levels) to reduce cholesterol synthesis and cause desmosterol accumulation; this effect is independent of DHCR24 protein levels, is specific to certain C-25 oxysterols, and overexpression of DHCR24 blunts this inhibition.","method":"Cell-based cholesterol and desmosterol quantification; DHCR24 overexpression; genetic and pharmacological manipulation of 24,25EC levels; multiple mammalian cell lines","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mammalian cell lines tested, genetic and pharmacological manipulation, overexpression rescue, oxysterol specificity analysis; single lab but multiple orthogonal methods","pmids":["22178193"],"is_preprint":false},{"year":2011,"finding":"CAR (constitutive androstane receptor) and PXR transactivate DHCR24 expression; a DR4 motif in the human DHCR24 distal promoter was identified as a binding site for the CAR/RXRα and PXR/RXRα heterodimers, mechanistically linking xenobiotic-responsive nuclear receptors to cholesterol biosynthesis.","method":"Reporter gene assays in hepatoma cells; electrophoretic mobility-shift assay (EMSA); mouse liver activation by phenobarbital; CAR activation in cultured human hepatocytes","journal":"Toxicology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA binding plus reporter assay plus in vivo mouse and primary human hepatocyte validation, single lab","pmids":["22101211"],"is_preprint":false},{"year":2012,"finding":"DHCR24 transcription is regulated primarily through SREBP-2 binding to two cooperative sterol regulatory elements (SREs) in its promoter, assisted by NF-Y binding sites; sterol depletion activates DHCR24 transcription via this SREBP-2 mechanism.","method":"Luciferase reporter assays; EMSA; chromatin immunoprecipitation (ChIP); sterol-depletion experiments","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus EMSA plus reporter assay, single lab, three orthogonal methods establishing same mechanism","pmids":["22809995"],"is_preprint":false},{"year":2012,"finding":"Full-length DHCR24 localizes to the ER membrane with an N-terminal luminal/C-terminal cytoplasmic orientation (established by fluorescent protease protection assay); the N-terminal transmembrane domain is essential for ER membrane targeting. ER membrane targeting is NOT required for its ROS scavenging activity but the anti-apoptotic function of DHCR24 is associated with its cleavage by caspase.","method":"Fluorescent protease protection (FPP) assay; TM-domain deletion mutants; H2DCFDA ROS measurement; confocal fluorescence microscopy; caspase activity assay","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct topology determination by FPP assay plus domain deletion mutagenesis, single lab","pmids":["22010141"],"is_preprint":false},{"year":2012,"finding":"DHCR24 promoter transcription is initiated from a single CpG-rich promoter regulated by DNA methylation in some cell types; histone deacetylase inhibition (sodium butyrate) increases DHCR24 expression by recruiting acetylated histones H3/H4 to an enhancer region at −1203/−665 bp, as demonstrated by ChIP.","method":"Reporter gene assays; ChIP with anti-acetyl-H3/H4 antibodies; HDAC inhibitor treatment; DNA methylation analysis","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus pharmacological HDAC inhibition, single lab","pmids":["20568014"],"is_preprint":false},{"year":2013,"finding":"DHCR24 activity is regulated post-translationally by phosphorylation: mutation of residues T110, Y299, and Y507 inhibits DHCR24 enzymatic activity; inhibitors of protein kinase C ablate DHCR24 activity through a different (non-annotated phosphorylation site) mechanism.","method":"Site-directed mutagenesis of phosphorylation sites; ectopic human DHCR24 activity assay in CHO-7 cells (with siRNA knockdown of endogenous hamster DHCR24); PKC inhibitor treatment","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme activity assay with site-directed mutagenesis plus pharmacological inhibition, rigorous system to isolate human DHCR24 activity","pmids":["24363437"],"is_preprint":false},{"year":2014,"finding":"DHCR24 overexpression protects neuronal N2A cells from ER stress-induced apoptosis by reducing caspase-12 activity, diminishing ER stress markers (Bip, CHOP), attenuating JNK/p38 activation, decreasing intracellular ROS, and promoting caveolae formation with improved caveolin-1/IGF1R co-localization.","method":"Adenoviral DHCR24 overexpression in N2A cells; tunicamycin-induced ER stress; caspase-12 assay; Western blotting for ER stress markers; H2DCFDA ROS assay; confocal microscopy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct overexpression with multiple orthogonal mechanistic readouts, single lab","pmids":["24489783"],"is_preprint":false},{"year":2015,"finding":"DHCR24 (seladin-1) maintains lipid raft integrity in the ischemic brain; genetic heterozygous deletion (Dhcr24+/−) or pharmacological inhibition enlarges infarct volume, increases neuroinflammatory mediators, and reduces the association of glutamate transporter EAAT2 with lipid rafts, impairing glutamate uptake.","method":"Dhcr24+/− mice with middle cerebral artery occlusion; U18666A pharmacological inhibition; infarct volume measurement; lipid raft fractionation Western blot; [3H]-glutamate uptake assay in astrocyte cultures","journal":"Stroke","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and pharmacological inhibition, in vivo infarct quantification, fractionation assay, and functional transport assay; multiple orthogonal methods","pmids":["26628388"],"is_preprint":false},{"year":2015,"finding":"DHCR24 and DHCR7 (7-dehydrocholesterol reductase) physically interact by co-immunoprecipitation; DHCR24 knockdown ablates DHCR7 enzymatic activity, and DHCR24 overexpression (functional form only) enhances DHCR7 activity, indicating a functional cholesterol 'metabolon' with substrate channeling.","method":"Co-immunoprecipitation; siRNA knockdown of DHCR24; DHCR7 enzymatic activity assay; overexpression of functional vs. non-functional DHCR24","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional interaction established by Co-IP and enzyme activity assay with mutagenesis control, single lab","pmids":["25637936"],"is_preprint":false},{"year":2017,"finding":"Insulin induces DHCR24 expression through STAT3, which directly binds to the DHCR24 promoter (demonstrated by ChIP-PCR and luciferase assay); silencing DHCR24 inhibits endometrial cancer cell metastasis and upregulates progesterone receptor (PGR) expression.","method":"ChIP-PCR; luciferase reporter assay; siRNA knockdown; cell migration assays; PGR Western blotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR plus luciferase reporter establishing STAT3 binding to DHCR24 promoter, plus functional KD assay, single lab","pmids":["28112250"],"is_preprint":false},{"year":2017,"finding":"DHCR24 overexpression protects neurons against LPS/IFN-γ-induced neuroinflammatory death in co-cultures and increases neuroligin-1 levels, dendritic spine density, and the proportion of mushroom spines; in vivo, DHCR24 overexpression in striatum reduces ischemic lesion size in a mouse transient focal ischemia model.","method":"Neuronal–microglial co-culture with LPS/IFN-γ; adeno-associated virus DHCR24 overexpression in vivo; MRI infarct measurement; dendritic spine morphology analysis; Western blotting for neuroligin-1","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro co-culture plus in vivo gene delivery with functional outcome measures, single lab","pmids":["29115990"],"is_preprint":false},{"year":2018,"finding":"Dhcr24 overexpression protects against dilated cardiomyopathy (DCM) in cTnTR141W transgenic mice by activating the PI3K/Akt/HKII pathway and reducing Bax translocation, cytochrome c release, and caspase-9/caspase-3 activation. PI3K inhibition completely removes the anti-apoptotic effect; HKII inhibition only partially reduces it.","method":"Heart-specific transgenic Dhcr24 overexpression in DCM mice; Western blotting for PI3K/Akt/HKII pathway; TUNEL assay; echocardiography; PI3K and HKII inhibitors in H9c2 cells","journal":"Animal models and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic overexpression with pathway epistasis via inhibitors, multiple apoptosis readouts, single lab","pmids":["30891546"],"is_preprint":false},{"year":2019,"finding":"miR-124 directly targets Dhcr24 in cardiomyocytes; miR-124 overexpression increases cardiomyocyte apoptosis, which is mediated through downregulation of Dhcr24; miR-124 inhibition attenuates cell death; the miR-124–Dhcr24 axis regulates oxidative stress- and hypoxia-induced cardiomyocyte apoptosis and myocardial infarction in vivo.","method":"miR-124 overexpression/inhibition in cardiomyocytes; 3'UTR luciferase reporter (implied by target identification); in vivo intra-myocardial agomiR/antagomiR injection; apoptosis assays","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — target validation plus in vivo miRNA manipulation, functional apoptosis readout; miRNA targeting assay details not fully described in abstract","pmids":["31100313"],"is_preprint":false},{"year":2020,"finding":"Genkwadaphnin (GD) suppresses DHCR24 expression and enzymatic activity, thereby inhibiting DHCR24-mediated cholesterol biosynthesis and lipid raft formation, which reduces HCC cell invasion and migration in vitro and tumor growth in vivo.","method":"DHCR24 siRNA knockdown; GD pharmacological inhibition; cholesterol level measurement; lipid raft structural assay; HCC xenograft in BALB/c nude mice; microarray gene expression","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological inhibition with multiple functional readouts in vitro and in vivo, single lab","pmids":["32958824"],"is_preprint":false},{"year":2020,"finding":"DHCR24 overexpression in BV-2 microglia treated with Aβ25-35 reverses M1 polarization toward M2 phenotype and activates the Akt/GSK3β signaling pathway; co-treatment with the Akt inhibitor MK2206 reverses the effect of DHCR24, placing DHCR24 upstream of Akt/GSK3β in microglial inflammatory regulation.","method":"Lentiviral DHCR24 overexpression in BV-2 cells; Western blotting for P-Akt and P-GSK3β; cytokine (iNOS, IL-1β, TNF-α, arginase-1, IL-4, TGF-β) measurement; Akt inhibitor epistasis","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression plus pharmacological epistasis, single lab, multiple polarization markers","pmids":["32950573"],"is_preprint":false},{"year":2021,"finding":"DHCR24 knockdown in SH-SY5Y cells reduces plasma membrane cholesterol and caveolin-1, disrupts lipid rafts/caveolae, decreases PI3-K/Akt signaling (reduced p-Akt at Thr308 and Ser473), activates GSK3β, and activates mTOR, leading to tau hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396 and inhibition of autophagy; DHCR24 knock-in reverses all these effects.","method":"siRNA knockdown and overexpression (knock-in); Western blotting for cholesterol, caveolin-1, p-Akt, p-GSK3β, p-mTOR, LC3-II/I, p62; phospho-tau Western blotting; autophagosome counting","journal":"Frontiers in aging neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (KD and KI) with multiple ordered pathway readouts, single lab","pmids":["33967735"],"is_preprint":false},{"year":2021,"finding":"DHCR24 knockdown in SH-SY5Y cells decreases plasma membrane cholesterol and caveolin-1, inhibiting PP2A activity (via increased p-PP2Ac at Y307) and activating GSK3β (via increased p-GSK3β at Y216), leading to tau hyperphosphorylation at multiple sites (Thr181, Thr231, Ser262, Ser396, Ser422); PP2A activator D-erythro-Sphingosine reverses the tau hyperphosphorylation induced by DHCR24 knockdown.","method":"siRNA knockdown and DHCR24 overexpression; Western blotting for PP2A activity markers, GSK3β, and phospho-tau; Filipin III cholesterol staining; PP2A activator rescue experiment","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation plus enzymatic rescue epistasis, single lab, multiple pathway nodes measured","pmids":["33710538"],"is_preprint":false},{"year":2022,"finding":"SOX9 directly transcriptionally activates DHCR24 expression in diffuse large B-cell lymphomas (DLBCL) bearing IGH-BCL2 translocations, as shown by whole-transcriptome analysis and ChIP-seq; enforced DHCR24 expression rescues cell proliferation after SOX9 knockdown; DHCR24 mediates SOX9-driven cholesterol synthesis and lymphomagenesis.","method":"Whole-transcriptome analysis; ChIP-seq; SOX9 siRNA knockdown; DHCR24 forced expression rescue; xenograft tumor model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq direct binding evidence plus epistatic rescue experiment in vitro and in vivo xenograft, multiple orthogonal methods","pmids":["34624089"],"is_preprint":false},{"year":2022,"finding":"SRSF3 directly regulates DHCR24 expression in colorectal cancer; SRSF3 silencing suppresses DHCR24, and the SRSF3 inhibitor SFI003 drives apoptosis via the SRSF3/DHCR24/ROS axis; elevated ROS upon DHCR24 reduction mediates the anticancer effect.","method":"SRSF3 siRNA knockdown; SFI003 pharmacological inhibition; DHCR24 expression measurement; ROS quantification; in vitro and in vivo xenograft assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological epistasis with functional ROS readout in vitro and in vivo, single lab","pmids":["35501301"],"is_preprint":false},{"year":2022,"finding":"DHCR24 knockdown in C8D1A astrocytes decreases cholesterol in plasma membrane and intracellular organelles, reduces caveola-associated protein cavin1, disrupts lipid rafts/caveolae, and activates the caveolae-dependent Ras/MEK/ERK signaling pathway, leading to tau hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396; DHCR24 overexpression prevents ERK overactivation and tau hyperphosphorylation.","method":"siRNA knockdown and overexpression in C8D1A astrocytes; Filipin III staining; Western blotting for cavin1, Ras/MEK/ERK pathway, phospho-tau; cholesterol quantification","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation in astrocytes with lipid raft disruption and signaling pathway readouts, single lab","pmids":["35804281"],"is_preprint":false},{"year":2023,"finding":"miR-7 post-transcriptionally suppresses DHCR24 expression by targeting its 3'UTR, thereby blocking the last steps of cholesterol biosynthesis; intracranial AAV-delivered miR-7 reduces DHCR24 in mouse brain. Cholesterol reciprocally regulates miR-7 levels through SREBP2-mediated transcription, establishing a feedback loop.","method":"In vitro miR-7 overexpression; AAV intracranial delivery in mice; DHCR24 expression measurement; SREBP2 ChIP on miR-7 host gene promoter; Niemann Pick C1 mouse model and fatty liver model","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo miRNA manipulation plus SREBP2 ChIP evidence for feedback regulation, single lab","pmids":["37086967"],"is_preprint":false},{"year":2023,"finding":"Pharmacological inhibition of DHCR24 by SH42 increases desmosterol in liver and plasma, activates LXRα, reduces hepatic lipid content and steatosis, decreases Kupffer cell activation and monocyte infiltration, and reduces liver collagen and ALT levels; LXRα deficiency completely abolishes all beneficial effects of SH42, placing DHCR24 upstream of LXRα in NAFLD/NASH regulation.","method":"APOE*3-Leiden.CETP mouse model; SH42 pharmacological inhibition; desmosterol quantification; flow cytometry; LXRα knockout mice; liver histology; collagen/ALT measurements","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological inhibition combined with LXRα KO genetic epistasis in a validated translational mouse model, multiple orthogonal functional readouts","pmids":["37357756"],"is_preprint":false},{"year":2023,"finding":"AAV-mediated DHCR24 overexpression in hippocampus of 5xFAD mice increases cholesterol, reverses cognitive impairment, reduces amyloid-β deposition, synaptic injury, autophagy dysfunction, reactive astrocytosis, microglial phagocytosis abnormalities, and apoptosis.","method":"AAV hippocampal delivery in 5xFAD mice; cholesterol quantification; behavioral tests; immunohistochemistry for Aβ, synaptic, autophagy, and apoptotic markers","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene delivery with multiple outcome measures in a validated AD model, single lab","pmids":["37344916"],"is_preprint":false}],"current_model":"DHCR24 (seladin-1) is an FAD-dependent oxidoreductase anchored to the ER membrane (N-terminal luminal, C-terminal cytoplasmic) that catalyzes the terminal conversion of desmosterol to cholesterol; its enzymatic activity—regulated transcriptionally by SREBP-2, LXR, CAR/PXR, AR, ER-alpha, and miR-7/miR-124, and post-translationally by phosphorylation at T110/Y299/Y507 and by oxysterol 24,25-epoxycholesterol—controls membrane cholesterol content and lipid raft/caveolae integrity, which in turn modulates multiple downstream signaling cascades (PI3K/Akt/Bad, Akt/GSK3β/mTOR, PP2A, Ras/MEK/ERK, EAAT2-mediated glutamate uptake); independently of cholesterol synthesis, DHCR24 stabilizes p53 by binding its N-terminus and displacing Mdm2, thereby mediating the cellular response to oncogenic and oxidative stress, and inhibits caspase-3 to confer neuroprotection against Aβ toxicity, ER stress, and neuroinflammation; DHCR24 additionally serves as an obligate host factor for HCV replication and functions upstream of LXRα to regulate hepatic lipid homeostasis and inflammation."},"narrative":{"mechanistic_narrative":"DHCR24 (seladin-1) is an FAD-dependent oxidoreductase of the ER membrane that catalyzes the terminal step of cholesterol biosynthesis, reducing desmosterol to cholesterol, and through this activity governs membrane cholesterol content and the integrity of cholesterol-rich detergent-resistant membrane domains (lipid rafts/caveolae) that organize downstream signaling [PMID:16410790, PMID:16407971, PMID:22178193]. The enzyme adopts an N-terminal-luminal/C-terminal-cytoplasmic ER topology, with its N-terminal transmembrane domain required for ER targeting; its catalytic activity depends on phosphorylatable residues T110, Y299, and Y507 and is acutely inhibited by the endogenous oxysterol 24(S),25-epoxycholesterol independently of protein level [PMID:22010141, PMID:24363437, PMID:22178193]. In vivo, DHCR24 loss is neonatally lethal with desmosterol-for-cholesterol replacement that disrupts epidermal differentiation and barrier function, establishing the enzyme's non-redundant role in cholesterol production [PMID:16410790]. By maintaining raft/caveolae integrity, DHCR24 sustains caveolin-1-dependent receptor signaling and survival cascades—including insulin/IGF1R-Akt-Bad, Akt/GSK3β/mTOR, PP2A, and Ras/MEK/ERK—such that its depletion disrupts these axes and drives tau hyperphosphorylation, while it also partners physically with DHCR7 in a cholesterol-synthesis metabolon [PMID:16513830, PMID:33967735, PMID:33710538, PMID:35804281, PMID:25637936]. Independently of cholesterol synthesis, DHCR24 binds the p53 N-terminus and displaces Mdm2 to stabilize p53, mediating responses to oncogenic and oxidative stress, and confers anti-apoptotic neuroprotection against amyloid-β, ER stress, and neuroinflammation in part by limiting caspase activation [PMID:15577914, PMID:17984220, PMID:24489783]. Its expression is controlled by a broad transcriptional network—SREBP-2, LXR, CAR/PXR, AR, ER-alpha, STAT3, SOX9—and by the microRNAs miR-7 and miR-124 [PMID:22809995, PMID:18815215, PMID:22101211, PMID:18762779, PMID:18499757, PMID:28112250, PMID:34624089, PMID:37086967, PMID:31100313]. DHCR24 functions upstream of LXRα in hepatic lipid and inflammatory homeostasis and serves as a required host factor for HCV replication [PMID:37357756, PMID:21184787].","teleology":[{"year":2000,"claim":"Established the first cellular function of seladin-1 as an anti-apoptotic neuroprotective factor, framing the gene beyond a metabolic enzyme.","evidence":"functional expression in H4 neuroglioma cells with caspase-3 activity assays and immunoblot","pmids":["11007892"],"confidence":"Medium","gaps":["Mechanism linking seladin-1 to caspase-3 inhibition not defined","Did not establish enzymatic basis or substrate"]},{"year":2004,"claim":"Revealed a cholesterol-independent tumor-suppressive mechanism: DHCR24 stabilizes p53 by binding its N-terminus and displacing Mdm2.","evidence":"genetic screen, reciprocal co-IP, interface mutagenesis, and transformation assays in fibroblasts","pmids":["15577914"],"confidence":"High","gaps":["Structural basis of p53/Mdm2 interface binding not resolved","Relationship between this moonlighting function and the reductase activity unclear"]},{"year":2006,"claim":"Defined DHCR24 as the enzyme catalyzing desmosterol→cholesterol conversion essential in vivo, and linked its loss to lipid raft disruption and amyloidogenic APP processing.","evidence":"DHCR24 knockout mouse brain and epidermis analysis with sterol quantification, DRM fractionation, BACE assays, and differentiation markers","pmids":["16407971","16410790"],"confidence":"High","gaps":["Enzyme kinetics and cofactor requirements not characterized here","Tissue-specific consequences beyond brain and skin not addressed"]},{"year":2006,"claim":"Connected DHCR24-dependent cholesterol to caveolae-organized insulin receptor/Akt-Bad survival signaling.","evidence":"DHCR24−/− MEFs with fractionation, phospho-Akt/Bad immunoblot, and cholesterol-repletion rescue","pmids":["16513830"],"confidence":"High","gaps":["Direct molecular link between cholesterol and IR-caveolin co-localization not resolved"]},{"year":2007,"claim":"Distinguished two protective modes—cholesterol-dependent oxidative-stress resistance and cholesterol-independent p53 stabilization—using catalytic mutants.","evidence":"SH-SY5Y overexpression with reductase-activity mutants, p53 ubiquitination assays, and primary neuron knockdown with p53 rescue","pmids":["17984220"],"confidence":"High","gaps":["How chronic stress switches between the two modes not defined"]},{"year":2008,"claim":"Mapped the transcriptional regulators of DHCR24, placing cholesterol synthesis under hormonal (ER-alpha, AR) and oxysterol (LXR) control.","evidence":"luciferase reporters, ChIP, promoter element analysis, and LXRβ-null/cell line expression","pmids":["18499757","18815215","18762779"],"confidence":"Medium","gaps":["Direct AR binding not assayed in some studies","Tissue-specific contribution of each regulator not quantified"]},{"year":2008,"claim":"Showed DHCR24-driven membrane cholesterol limits amyloid-β plasma-membrane accumulation and calcium dysregulation.","evidence":"SH-SY5Y overexpression and seladin-1 inhibitor treatment with confocal Aβ imaging and Ca2+ imaging","pmids":["18194465"],"confidence":"Medium","gaps":["Pharmacological inhibitor specificity not fully controlled","Direct membrane interaction mechanism not shown"]},{"year":2009,"claim":"Ordered the caspase-3/GGA3/BACE1 axis downstream of seladin-1 loss under apoptotic conditions, linking apoptosis to amyloidogenesis.","evidence":"siRNA knockdown in SH-SY5Y with caspase-3 assays, GGA3/BACE1 immunoblot, and Aβ ELISA","pmids":["19815556"],"confidence":"Medium","gaps":["Effect confined to apoptotic conditions; physiological relevance unclear"]},{"year":2009,"claim":"Documented ACTH-induced nuclear relocalization of seladin-1 and a steroidogenic role in adrenal DHEA secretion.","evidence":"immunofluorescence, fractionation, U18666A inhibition, and steroid ELISA in rat and human fasciculata cells","pmids":["19520779"],"confidence":"Medium","gaps":["Functional significance of nuclear relocalization not established","Species differences in localization unexplained"]},{"year":2010,"claim":"Identified DHCR24 as an obligate host factor for HCV replication and a druggable antiviral target.","evidence":"siRNA knockdown and U18666A inhibition in replicon/JFH-1 systems and humanized chimeric mice","pmids":["21184787"],"confidence":"High","gaps":["Molecular step in HCV replication requiring DHCR24 not defined"]},{"year":2011,"claim":"Established post-translational and additional transcriptional control of DHCR24: acute oxysterol inhibition of activity and CAR/PXR transactivation.","evidence":"cell-based sterol quantification with overexpression rescue; reporter assays, EMSA, and in vivo phenobarbital induction","pmids":["22178193","22101211"],"confidence":"High","gaps":["Molecular mechanism of 24,25EC inhibition of the enzyme not resolved"]},{"year":2012,"claim":"Resolved DHCR24 transcriptional, epigenetic, and topological regulation, establishing SREBP-2/NF-Y control, methylation/HDAC sensitivity, and ER membrane orientation.","evidence":"reporter assays, EMSA, ChIP, methylation analysis, and fluorescent protease protection topology assay","pmids":["22809995","20568014","22010141"],"confidence":"Medium","gaps":["Functional consequence of ER topology for catalysis not defined","ER targeting dispensable for ROS scavenging—alternate localization not mapped"]},{"year":2013,"claim":"Identified specific phosphorylation sites (T110, Y299, Y507) and PKC-dependent regulation as post-translational controls of reductase activity.","evidence":"site-directed mutagenesis with ectopic human DHCR24 activity assay in CHO-7 cells and PKC inhibitor treatment","pmids":["24363437"],"confidence":"High","gaps":["Responsible kinases not identified","Phosphorylation stoichiometry under physiological signaling unknown"]},{"year":2015,"claim":"Demonstrated a DHCR24-DHCR7 cholesterol metabolon and a brain-protective raft function maintaining EAAT2-mediated glutamate uptake.","evidence":"co-IP and reciprocal enzyme activity assays; Dhcr24+/− MCAO mice with raft fractionation and glutamate uptake assays","pmids":["25637936","26628388"],"confidence":"Medium","gaps":["Direct substrate channeling between DHCR24 and DHCR7 not visualized","Stoichiometry of the metabolon unknown"]},{"year":2017,"claim":"Extended DHCR24 transcriptional control to insulin/STAT3 and linked it to cancer cell behavior.","evidence":"ChIP-PCR, luciferase reporter, siRNA knockdown, and migration assays in endometrial cancer cells","pmids":["28112250"],"confidence":"Medium","gaps":["Whether metastatic effect depends on cholesterol synthesis vs. moonlighting function not separated"]},{"year":2018,"claim":"Mapped DHCR24 cardioprotection through PI3K/Akt/HKII anti-apoptotic signaling in dilated cardiomyopathy.","evidence":"heart-specific transgenic overexpression in DCM mice with pathway epistasis by PI3K/HKII inhibitors and apoptosis readouts","pmids":["30891546"],"confidence":"Medium","gaps":["Whether protection requires cholesterol synthesis not tested with catalytic mutants"]},{"year":2019,"claim":"Identified the miR-124–Dhcr24 axis controlling cardiomyocyte apoptosis and infarction.","evidence":"miR-124 gain/loss in cardiomyocytes, 3'UTR reporter, and in vivo agomiR/antagomiR injection with apoptosis assays","pmids":["31100313"],"confidence":"Medium","gaps":["miRNA targeting assay details limited","Direct 3'UTR binding only implied"]},{"year":2020,"claim":"Consolidated DHCR24 as an upstream regulator of microglial polarization (Akt/GSK3β) and as a cholesterol/raft-dependent driver of HCC invasion.","evidence":"lentiviral/siRNA manipulation with Akt-inhibitor epistasis in BV-2 cells; siRNA and genkwadaphnin inhibition with raft and xenograft assays in HCC","pmids":["32950573","32958824"],"confidence":"Medium","gaps":["Direct molecular link from DHCR24 to Akt activation not defined"]},{"year":2021,"claim":"Defined the cholesterol/caveolae → Akt-GSK3β-mTOR and PP2A signaling cascades whose disruption by DHCR24 loss drives tau hyperphosphorylation and impaired autophagy.","evidence":"bidirectional knockdown/knock-in in SH-SY5Y with phospho-tau, PP2A/GSK3β markers, autophagy readouts, and enzymatic rescue","pmids":["33967735","33710538"],"confidence":"Medium","gaps":["Causal hierarchy among Akt, PP2A, and mTOR nodes not fully ordered","In vivo relevance to tauopathy not tested here"]},{"year":2022,"claim":"Extended raft-dependent signaling to astrocytic Ras/MEK/ERK-driven tau pathology and identified SOX9 and SRSF3 as cancer-context regulators of DHCR24.","evidence":"bidirectional manipulation in astrocytes; ChIP-seq/rescue (SOX9) and siRNA/SFI003 ROS-axis assays (SRSF3) with xenografts","pmids":["35804281","34624089","35501301"],"confidence":"Medium","gaps":["Cell-type specificity of each upstream regulator not generalized","Whether ROS effects are downstream of cholesterol loss vs. moonlighting not separated"]},{"year":2023,"claim":"Established DHCR24 as upstream of LXRα in hepatic lipid/inflammation control, identified a miR-7–cholesterol feedback loop, and demonstrated in vivo neuroprotection in an AD model.","evidence":"SH42 inhibition with LXRα-KO epistasis in APOE*3-Leiden.CETP mice; miR-7 manipulation with SREBP2 ChIP; AAV DHCR24 overexpression in 5xFAD mice","pmids":["37357756","37086967","37344916"],"confidence":"High","gaps":["Mechanism by which desmosterol activates LXRα in vivo not fully dissected","Translational dosing/safety of DHCR24 modulation unaddressed"]},{"year":null,"claim":"How DHCR24's catalytic (cholesterol-synthesis) and moonlighting (p53-stabilizing, anti-caspase) functions are coordinated, and which is required in each disease context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the enzyme or its p53/Mdm2 interface","No clean separation-of-function genetics across tissues","Kinases and signals controlling phosphorylation-dependent activity unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,13,18,21]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[16,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,28,32]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,13,34]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,5,19,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,28,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,30]}],"complexes":["DHCR24-DHCR7 cholesterol metabolon"],"partners":["TP53","MDM2","DHCR7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15392","full_name":"Delta(24)-sterol reductase","aliases":["24-dehydrocholesterol reductase","3-beta-hydroxysterol Delta-24-reductase","Diminuto/dwarf1 homolog","Seladin-1"],"length_aa":516,"mass_kda":60.1,"function":"Catalyzes the reduction of the delta-24 double bond of sterol intermediates during cholesterol biosynthesis (PubMed:11519011, PubMed:21671375, PubMed:22178193, PubMed:25637936). In addition to its cholesterol-synthesizing activity, can protect cells from oxidative stress by reducing caspase 3 activity during apoptosis induced by oxidative stress (PubMed:11007892, PubMed:22010141). Also protects against amyloid-beta peptide-induced apoptosis (PubMed:11007892)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q15392/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DHCR24","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000116133","cell_line_id":"CID000292","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2},{"gene":"EBP","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000292","total_profiled":1310},"omim":[{"mim_id":"606418","title":"24-@DEHYDROCHOLESTEROL REDUCTASE; DHCR24","url":"https://www.omim.org/entry/606418"},{"mim_id":"602398","title":"DESMOSTEROLOSIS","url":"https://www.omim.org/entry/602398"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":1055.0},{"tissue":"liver","ntpm":583.3}],"url":"https://www.proteinatlas.org/search/DHCR24"},"hgnc":{"alias_symbol":["KIAA0018","seladin-1"],"prev_symbol":["DCE"]},"alphafold":{"accession":"Q15392","domains":[{"cath_id":"3.30.465.10","chopping":"62-234","consensus_level":"medium","plddt":94.5709,"start":62,"end":234},{"cath_id":"-","chopping":"238-373","consensus_level":"medium","plddt":94.3155,"start":238,"end":373},{"cath_id":"3.30.70,3.30.70","chopping":"379-482","consensus_level":"medium","plddt":92.9391,"start":379,"end":482}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15392","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15392-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15392-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DHCR24","jax_strain_url":"https://www.jax.org/strain/search?query=DHCR24"},"sequence":{"accession":"Q15392","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15392.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15392/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15392"}},"corpus_meta":[{"pmid":"28521821","id":"PMC_28521821","title":"Intratumoral and peritumoral radiomics for the pretreatment prediction of pathological complete response to neoadjuvant chemotherapy based on breast DCE-MRI.","date":"2017","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/28521821","citation_count":512,"is_preprint":false},{"pmid":"11007892","id":"PMC_11007892","title":"The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress.","date":"2000","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11007892","citation_count":240,"is_preprint":false},{"pmid":"15577914","id":"PMC_15577914","title":"Regulation of cellular response to oncogenic and oxidative stress by Seladin-1.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15577914","citation_count":165,"is_preprint":false},{"pmid":"16407971","id":"PMC_16407971","title":"The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16407971","citation_count":152,"is_preprint":false},{"pmid":"24095826","id":"PMC_24095826","title":"Desmosterol and DHCR24: unexpected new directions for a terminal step in cholesterol synthesis.","date":"2013","source":"Progress in lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/24095826","citation_count":134,"is_preprint":false},{"pmid":"18376462","id":"PMC_18376462","title":"Dynamic contrast-enhanced ultrasonography (DCE-US) with quantification of tumor perfusion: a new diagnostic tool to evaluate the early effects of antiangiogenic treatment.","date":"2007","source":"European radiology","url":"https://pubmed.ncbi.nlm.nih.gov/18376462","citation_count":111,"is_preprint":false},{"pmid":"20379790","id":"PMC_20379790","title":"Dynamic contrast-enhanced ultrasonography (DCE-US): a new tool for the early evaluation of antiangiogenic treatment.","date":"2010","source":"Targeted oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20379790","citation_count":80,"is_preprint":false},{"pmid":"12127087","id":"PMC_12127087","title":"Seladin-1 transcription is linked to neuronal degeneration in Alzheimer's disease.","date":"2002","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12127087","citation_count":79,"is_preprint":false},{"pmid":"17984220","id":"PMC_17984220","title":"Prosurvival effect of DHCR24/Seladin-1 in acute and chronic responses to oxidative stress.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17984220","citation_count":78,"is_preprint":false},{"pmid":"29970244","id":"PMC_29970244","title":"Breast cancer Ki67 expression prediction by DCE-MRI radiomics features.","date":"2018","source":"Clinical radiology","url":"https://pubmed.ncbi.nlm.nih.gov/29970244","citation_count":78,"is_preprint":false},{"pmid":"25637936","id":"PMC_25637936","title":"The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact physically and functionally.","date":"2015","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/25637936","citation_count":76,"is_preprint":false},{"pmid":"16410790","id":"PMC_16410790","title":"DHCR24 gene knockout mice demonstrate lethal dermopathy with differentiation and maturation defects in the epidermis.","date":"2006","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/16410790","citation_count":63,"is_preprint":false},{"pmid":"24363437","id":"PMC_24363437","title":"Signaling regulates activity of DHCR24, the final enzyme in cholesterol synthesis.","date":"2013","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/24363437","citation_count":63,"is_preprint":false},{"pmid":"21224376","id":"PMC_21224376","title":"Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib.","date":"2011","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/21224376","citation_count":61,"is_preprint":false},{"pmid":"18768664","id":"PMC_18768664","title":"Neuroprotective effects of the Alzheimer's disease-related gene seladin-1.","date":"2008","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18768664","citation_count":60,"is_preprint":false},{"pmid":"18499757","id":"PMC_18499757","title":"Seladin-1 is a fundamental mediator of the neuroprotective effects of estrogen in human neuroblast long-term cell cultures.","date":"2008","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18499757","citation_count":60,"is_preprint":false},{"pmid":"19815556","id":"PMC_19815556","title":"Down-regulation of seladin-1 increases BACE1 levels and activity through enhanced GGA3 depletion during apoptosis.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19815556","citation_count":59,"is_preprint":false},{"pmid":"16762343","id":"PMC_16762343","title":"Neuronal differentiation of human mesenchymal stem cells: changes in the expression of the Alzheimer's disease-related gene seladin-1.","date":"2006","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/16762343","citation_count":58,"is_preprint":false},{"pmid":"28488024","id":"PMC_28488024","title":"Glioma Grading and Determination of IDH Mutation Status and ATRX loss by DCE and ASL Perfusion.","date":"2017","source":"Clinical neuroradiology","url":"https://pubmed.ncbi.nlm.nih.gov/28488024","citation_count":57,"is_preprint":false},{"pmid":"21184787","id":"PMC_21184787","title":"Augmentation of DHCR24 expression by hepatitis C virus infection facilitates viral replication in hepatocytes.","date":"2010","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/21184787","citation_count":56,"is_preprint":false},{"pmid":"18194465","id":"PMC_18194465","title":"Seladin-1/DHCR24 protects neuroblastoma cells against Abeta toxicity by increasing membrane cholesterol content.","date":"2008","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18194465","citation_count":54,"is_preprint":false},{"pmid":"27888709","id":"PMC_27888709","title":"Correlations Between DCE MRI and Histopathological Parameters in Head and Neck Squamous Cell Carcinoma.","date":"2016","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27888709","citation_count":54,"is_preprint":false},{"pmid":"16091489","id":"PMC_16091489","title":"Expression of the antiapoptotic gene seladin-1 and octreotide-induced apoptosis in growth hormone-secreting and nonfunctioning pituitary adenomas.","date":"2005","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/16091489","citation_count":52,"is_preprint":false},{"pmid":"31100313","id":"PMC_31100313","title":"MicroRNA-124 regulates cardiomyocyte apoptosis and myocardial infarction through targeting Dhcr24.","date":"2019","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/31100313","citation_count":50,"is_preprint":false},{"pmid":"17149623","id":"PMC_17149623","title":"Relationship between DCE-MRI morphological and functional features and histopathological characteristics of breast cancer.","date":"2006","source":"European radiology","url":"https://pubmed.ncbi.nlm.nih.gov/17149623","citation_count":50,"is_preprint":false},{"pmid":"22366441","id":"PMC_22366441","title":"Correlation of a priori DCE-MRI and (1)H-MRS data with molecular markers in neck nodal metastases: Initial analysis.","date":"2012","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22366441","citation_count":50,"is_preprint":false},{"pmid":"28112250","id":"PMC_28112250","title":"Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28112250","citation_count":49,"is_preprint":false},{"pmid":"31372786","id":"PMC_31372786","title":"Differential diagnosis of nasopharyngeal carcinoma and nasopharyngeal lymphoma based on DCE-MRI and RESOLVE-DWI.","date":"2019","source":"European radiology","url":"https://pubmed.ncbi.nlm.nih.gov/31372786","citation_count":49,"is_preprint":false},{"pmid":"35595629","id":"PMC_35595629","title":"DCE-MRI Radiomics Analysis in Differentiating Luminal A and Luminal B Breast Cancer Molecular Subtypes.","date":"2022","source":"Academic radiology","url":"https://pubmed.ncbi.nlm.nih.gov/35595629","citation_count":48,"is_preprint":false},{"pmid":"32958824","id":"PMC_32958824","title":"Genkwadaphnin inhibits growth and invasion in hepatocellular carcinoma by blocking DHCR24-mediated cholesterol biosynthesis and lipid rafts formation.","date":"2020","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32958824","citation_count":47,"is_preprint":false},{"pmid":"16513830","id":"PMC_16513830","title":"DHCR24-knockout embryonic fibroblasts are susceptible to serum withdrawal-induced apoptosis because of dysfunction of caveolae and insulin-Akt-Bad signaling.","date":"2006","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/16513830","citation_count":47,"is_preprint":false},{"pmid":"22178193","id":"PMC_22178193","title":"The endogenous regulator 24(S),25-epoxycholesterol inhibits cholesterol synthesis at DHCR24 (Seladin-1).","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22178193","citation_count":46,"is_preprint":false},{"pmid":"35296367","id":"PMC_35296367","title":"The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis.","date":"2022","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/35296367","citation_count":45,"is_preprint":false},{"pmid":"29115990","id":"PMC_29115990","title":"DHCR24 exerts neuroprotection upon inflammation-induced neuronal death.","date":"2017","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/29115990","citation_count":45,"is_preprint":false},{"pmid":"31983532","id":"PMC_31983532","title":"DSC and DCE Histogram Analyses of Glioma Biomarkers, Including IDH, MGMT, and TERT, on Differentiation and Survival.","date":"2020","source":"Academic radiology","url":"https://pubmed.ncbi.nlm.nih.gov/31983532","citation_count":45,"is_preprint":false},{"pmid":"31392480","id":"PMC_31392480","title":"Gastric cancer and image-derived quantitative parameters: Part 2-a critical review of DCE-MRI and 18F-FDG PET/CT findings.","date":"2019","source":"European radiology","url":"https://pubmed.ncbi.nlm.nih.gov/31392480","citation_count":44,"is_preprint":false},{"pmid":"18762779","id":"PMC_18762779","title":"Androgen receptor regulation of the seladin-1/DHCR24 gene: altered expression in prostate cancer.","date":"2008","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18762779","citation_count":43,"is_preprint":false},{"pmid":"18815215","id":"PMC_18815215","title":"The selective Alzheimer's disease indicator-1 gene (Seladin-1/DHCR24) is a liver X receptor target gene.","date":"2008","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18815215","citation_count":41,"is_preprint":false},{"pmid":"18434374","id":"PMC_18434374","title":"Thyroid hormones promote cell differentiation and up-regulate the expression of the seladin-1 gene in in vitro models of human neuronal precursors.","date":"2008","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18434374","citation_count":40,"is_preprint":false},{"pmid":"30250576","id":"PMC_30250576","title":"Correlation between DCE-MRI radiomics features and Ki-67 expression in invasive breast cancer.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30250576","citation_count":40,"is_preprint":false},{"pmid":"34624089","id":"PMC_34624089","title":"Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2+ diffuse large B-cell lymphomas.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34624089","citation_count":38,"is_preprint":false},{"pmid":"18612048","id":"PMC_18612048","title":"Intermittent high glucose concentrations reduce neuronal precursor survival by altering the IGF system: the involvement of the neuroprotective factor DHCR24 (Seladin-1).","date":"2008","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18612048","citation_count":35,"is_preprint":false},{"pmid":"24489783","id":"PMC_24489783","title":"3 β-hydroxysteroid-Δ 24 reductase (DHCR24) protects neuronal cells from apoptotic cell death induced by endoplasmic reticulum (ER) stress.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24489783","citation_count":34,"is_preprint":false},{"pmid":"37357756","id":"PMC_37357756","title":"Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.","date":"2023","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37357756","citation_count":33,"is_preprint":false},{"pmid":"22809995","id":"PMC_22809995","title":"Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22809995","citation_count":33,"is_preprint":false},{"pmid":"30718984","id":"PMC_30718984","title":"Associations between Histogram Analysis Parameters Derived from DCE-MRI and Histopathological Features including Expression of EGFR, p16, VEGF, Hif1-alpha, and p53 in HNSCC.","date":"2019","source":"Contrast media & molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/30718984","citation_count":33,"is_preprint":false},{"pmid":"33967735","id":"PMC_33967735","title":"DHCR24 Knock-Down Induced Tau Hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396 Epitopes and Inhibition of Autophagy by Overactivation of GSK3β/mTOR Signaling.","date":"2021","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33967735","citation_count":31,"is_preprint":false},{"pmid":"31461951","id":"PMC_31461951","title":"Neuroinflammatory Reactions in the Brain of 1,2-DCE-Intoxicated Mice during Brain Edema.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31461951","citation_count":31,"is_preprint":false},{"pmid":"33900414","id":"PMC_33900414","title":"DCE-MRI in Glioma, Infiltration Zone and Healthy Brain to Assess Angiogenesis: A Biopsy Study.","date":"2021","source":"Clinical neuroradiology","url":"https://pubmed.ncbi.nlm.nih.gov/33900414","citation_count":31,"is_preprint":false},{"pmid":"34592360","id":"PMC_34592360","title":"DCE-MRI quantitative transport mapping for noninvasively detecting hypoxia inducible factor-1α, epidermal growth factor receptor overexpression, and Ki-67 in nasopharyngeal carcinoma patients.","date":"2021","source":"Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34592360","citation_count":30,"is_preprint":false},{"pmid":"19351544","id":"PMC_19351544","title":"New insights on the neuroprotective role of sterols and sex steroids: the seladin-1/DHCR24 paradigm.","date":"2009","source":"Frontiers in neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19351544","citation_count":28,"is_preprint":false},{"pmid":"37344916","id":"PMC_37344916","title":"DHCR24 reverses Alzheimer's disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice.","date":"2023","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/37344916","citation_count":28,"is_preprint":false},{"pmid":"22010141","id":"PMC_22010141","title":"The membrane topological analysis of 3β-hydroxysteroid-Delta24 reductase (DHCR24) on endoplasmic reticulum.","date":"2012","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22010141","citation_count":27,"is_preprint":false},{"pmid":"38649789","id":"PMC_38649789","title":"TREM2 alleviates white matter injury after traumatic brain injury in mice might be mediated by regulation of DHCR24/LXR pathway in microglia.","date":"2024","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38649789","citation_count":26,"is_preprint":false},{"pmid":"35501301","id":"PMC_35501301","title":"A novel SRSF3 inhibitor, SFI003, exerts anticancer activity against colorectal cancer by modulating the SRSF3/DHCR24/ROS axis.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35501301","citation_count":26,"is_preprint":false},{"pmid":"32950573","id":"PMC_32950573","title":"DHCR24 overexpression modulates microglia polarization and inflammatory response via Akt/GSK3β signaling in Aβ25-35 treated BV-2 cells.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32950573","citation_count":25,"is_preprint":false},{"pmid":"34995947","id":"PMC_34995947","title":"A radiomics model based on DCE-MRI and DWI may improve the prediction of estimating IDH1 mutation and angiogenesis in gliomas.","date":"2022","source":"European journal of radiology","url":"https://pubmed.ncbi.nlm.nih.gov/34995947","citation_count":25,"is_preprint":false},{"pmid":"20568014","id":"PMC_20568014","title":"Identification and analysis of the promoter region of the human DHCR24 gene: involvement of DNA methylation and histone acetylation.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20568014","citation_count":25,"is_preprint":false},{"pmid":"15963070","id":"PMC_15963070","title":"Seladin-1/DHCR24 expression in normal ovary, ovarian epithelial and granulosa tumours.","date":"2005","source":"Clinical endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15963070","citation_count":23,"is_preprint":false},{"pmid":"20166102","id":"PMC_20166102","title":"Inhibition of DHCR24/seladin-1 impairs cellular homeostasis in prostate cancer.","date":"2010","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/20166102","citation_count":23,"is_preprint":false},{"pmid":"22387408","id":"PMC_22387408","title":"Is seladin-1 really a selective Alzheimer's disease indicator?","date":"2012","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/22387408","citation_count":23,"is_preprint":false},{"pmid":"34781860","id":"PMC_34781860","title":"Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options.","date":"2022","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34781860","citation_count":23,"is_preprint":false},{"pmid":"18241265","id":"PMC_18241265","title":"Increased expression of aquaporin-3 in the epidermis of DHCR24 knockout mice.","date":"2008","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/18241265","citation_count":23,"is_preprint":false},{"pmid":"35804281","id":"PMC_35804281","title":"DHCR24 Knockdown Induces Tau Hyperphosphorylation at Thr181, Ser199, Ser262, and Ser396 Sites via Activation of the Lipid Raft-Dependent Ras/MEK/ERK Signaling Pathway in C8D1A Astrocytes.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35804281","citation_count":23,"is_preprint":false},{"pmid":"26628388","id":"PMC_26628388","title":"Seladin-1/DHCR24 Is Neuroprotective by Associating EAAT2 Glutamate Transporter to Lipid Rafts in Experimental Stroke.","date":"2015","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/26628388","citation_count":22,"is_preprint":false},{"pmid":"29731895","id":"PMC_29731895","title":"Upregulation of seladin-1 and nestin expression in bone marrow mesenchymal stem cell transplantation via the ERK1/2 and PI3K/Akt signaling pathways in an Alzheimer's disease model.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29731895","citation_count":22,"is_preprint":false},{"pmid":"30891546","id":"PMC_30891546","title":"Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice.","date":"2018","source":"Animal models and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30891546","citation_count":20,"is_preprint":false},{"pmid":"19520779","id":"PMC_19520779","title":"24-dehydrocholesterol reductase/seladin-1: a key protein differentially involved in adrenocorticotropin effects observed in human and rat adrenal cortex.","date":"2009","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19520779","citation_count":20,"is_preprint":false},{"pmid":"22101211","id":"PMC_22101211","title":"Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase.","date":"2011","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/22101211","citation_count":20,"is_preprint":false},{"pmid":"17510943","id":"PMC_17510943","title":"The association study between DHCR24 polymorphisms and Alzheimer's disease.","date":"2007","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17510943","citation_count":20,"is_preprint":false},{"pmid":"18394665","id":"PMC_18394665","title":"Homology modelling of human DHCR24 (seladin-1) and analysis of its binding properties through molecular docking and dynamics simulations.","date":"2008","source":"Steroids","url":"https://pubmed.ncbi.nlm.nih.gov/18394665","citation_count":20,"is_preprint":false},{"pmid":"23050906","id":"PMC_23050906","title":"Promoter analysis of the DHCR24 (3β-hydroxysterol Δ(24)-reductase) gene: characterization of SREBP (sterol-regulatory-element-binding protein)-mediated activation.","date":"2012","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/23050906","citation_count":20,"is_preprint":false},{"pmid":"17210742","id":"PMC_17210742","title":"Seladin-1 expression in rat adrenal gland: effect of adrenocorticotropic hormone treatment.","date":"2007","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17210742","citation_count":19,"is_preprint":false},{"pmid":"28856728","id":"PMC_28856728","title":"Data-driven mapping of hypoxia-related tumor heterogeneity using DCE-MRI and OE-MRI.","date":"2017","source":"Magnetic resonance in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28856728","citation_count":19,"is_preprint":false},{"pmid":"38745321","id":"PMC_38745321","title":"Enhancing pathological complete response prediction in breast cancer: the role of dynamic characterization of DCE-MRI and its association with tumor heterogeneity.","date":"2024","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/38745321","citation_count":19,"is_preprint":false},{"pmid":"28963049","id":"PMC_28963049","title":"Histogram analysis parameters identify multiple associations between DWI and DCE MRI in head and neck squamous cell carcinoma.","date":"2017","source":"Magnetic resonance imaging","url":"https://pubmed.ncbi.nlm.nih.gov/28963049","citation_count":18,"is_preprint":false},{"pmid":"33725777","id":"PMC_33725777","title":"Dynamic contrast-enhanced MRI of nasopharyngeal carcinoma: correlation of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters with hypoxia-inducible factor 1α expression and tumor grade/stage.","date":"2021","source":"Annals of palliative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33725777","citation_count":18,"is_preprint":false},{"pmid":"25347962","id":"PMC_25347962","title":"DHT inhibits the Aβ25-35-induced apoptosis by regulation of seladin-1, survivin, XIAP, bax, and bcl-xl expression through a rapid PI3-K/Akt signaling in C6 glial cell lines.","date":"2014","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/25347962","citation_count":17,"is_preprint":false},{"pmid":"32544519","id":"PMC_32544519","title":"The effect of baicalein-loaded Y-shaped miktoarm copolymer on spatial memory and hippocampal expression of DHCR24, SELADIN and SIRT6 genes in rat model of Alzheimer.","date":"2020","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/32544519","citation_count":17,"is_preprint":false},{"pmid":"25541351","id":"PMC_25541351","title":"Hippocampal DHCR24 down regulation in a rat model of streptozotocin-induced cognitive decline.","date":"2014","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/25541351","citation_count":17,"is_preprint":false},{"pmid":"31320461","id":"PMC_31320461","title":"Detection of Local Recurrence in Patients with Head and Neck Squamous Cell Carcinoma Using Voxel-Based Color Maps of Initial and Final Area under the Curve Values Derived from DCE-MRI.","date":"2019","source":"AJNR. American journal of neuroradiology","url":"https://pubmed.ncbi.nlm.nih.gov/31320461","citation_count":17,"is_preprint":false},{"pmid":"37086967","id":"PMC_37086967","title":"\"MiR-7 controls cholesterol biosynthesis through posttranscriptional regulation of DHCR24 expression\".","date":"2023","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/37086967","citation_count":15,"is_preprint":false},{"pmid":"31926979","id":"PMC_31926979","title":"Effects of chronic hypoxia on the expression of seladin-1/Tuj1 and the number of dark neurons of hippocampus.","date":"2020","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/31926979","citation_count":15,"is_preprint":false},{"pmid":"38847653","id":"PMC_38847653","title":"DHCR24 in Tumor Diagnosis and Treatment: A Comprehensive Review.","date":"2024","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/38847653","citation_count":14,"is_preprint":false},{"pmid":"19844922","id":"PMC_19844922","title":"Seladin-1 and testicular germ cell tumours: new insights into cisplatin responsiveness.","date":"2009","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19844922","citation_count":14,"is_preprint":false},{"pmid":"22405892","id":"PMC_22405892","title":"Testosterone up-regulates seladin-1 expression by iAR and PI3-K/Akt signaling pathway in C6 cells.","date":"2012","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/22405892","citation_count":14,"is_preprint":false},{"pmid":"31091460","id":"PMC_31091460","title":"Inhibition of DHCR24 increases the cisplatin-induced damage to cochlear hair cells in vitro.","date":"2019","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/31091460","citation_count":14,"is_preprint":false},{"pmid":"26288822","id":"PMC_26288822","title":"Serum DHCR24 Auto-antibody as a new Biomarker for Progression of Hepatitis C.","date":"2015","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/26288822","citation_count":14,"is_preprint":false},{"pmid":"33710538","id":"PMC_33710538","title":"DHCR24 Knockdown Lead to Hyperphosphorylation of Tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites by Membrane Lipid-Raft Dependent PP2A Signaling in SH-SY5Y Cells.","date":"2021","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/33710538","citation_count":14,"is_preprint":false},{"pmid":"24562935","id":"PMC_24562935","title":"DHCR24 is an independent predictor of progression in patients with non-muscle-invasive urothelial carcinoma, and its functional role is involved in the aggressive properties of urothelial carcinoma cells.","date":"2014","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24562935","citation_count":14,"is_preprint":false},{"pmid":"19597241","id":"PMC_19597241","title":"[Seladin-1/DHCR24: a key protein of cell homeostasis and cholesterol biosynthesis].","date":"2009","source":"Postepy higieny i medycyny doswiadczalnej (Online)","url":"https://pubmed.ncbi.nlm.nih.gov/19597241","citation_count":13,"is_preprint":false},{"pmid":"21987590","id":"PMC_21987590","title":"Simvastatin modulates the Alzheimer's disease-related gene seladin-1.","date":"2012","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/21987590","citation_count":13,"is_preprint":false},{"pmid":"30569161","id":"PMC_30569161","title":"Apolipoprotein M induces inhibition of inflammatory responses via the S1PR1 and DHCR24 pathways.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/30569161","citation_count":13,"is_preprint":false},{"pmid":"32734484","id":"PMC_32734484","title":"18F-FDG PET and DCE kinetic modeling and their correlations in primary NSCLC: first voxel-wise correlative analysis of human simultaneous [18F]FDG PET-MRI data.","date":"2020","source":"EJNMMI research","url":"https://pubmed.ncbi.nlm.nih.gov/32734484","citation_count":13,"is_preprint":false},{"pmid":"35639715","id":"PMC_35639715","title":"Diagnosis and differential diagnosis of dermatofibrosarcoma protuberans: Utility of high-resolution dynamic contrast-enhanced (DCE) MRI.","date":"2022","source":"Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)","url":"https://pubmed.ncbi.nlm.nih.gov/35639715","citation_count":13,"is_preprint":false},{"pmid":"34537053","id":"PMC_34537053","title":"Potential of combination of DCE-MRI and DWI with serum CA125 and CA199 in evaluating effectiveness of neoadjuvant chemotherapy in breast cancer.","date":"2021","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34537053","citation_count":13,"is_preprint":false},{"pmid":"31858293","id":"PMC_31858293","title":"Quantifying disease activity in rheumatoid arthritis with the TSPO PET ligand 18F-GE-180 and comparison with 18F-FDG and DCE-MRI.","date":"2019","source":"EJNMMI research","url":"https://pubmed.ncbi.nlm.nih.gov/31858293","citation_count":13,"is_preprint":false},{"pmid":"36468862","id":"PMC_36468862","title":"Augmentation of 3β-hydroxysteroid-Δ24 Reductase (DHCR24) Expression Induced by Bovine Viral Diarrhea Virus Infection Facilitates Viral Replication via Promoting Cholesterol Synthesis.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/36468862","citation_count":12,"is_preprint":false},{"pmid":"36106114","id":"PMC_36106114","title":"DCE-MRI radiomics models predicting the expression of radioresistant-related factors of LRP-1 and survivin in locally advanced rectal cancer.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36106114","citation_count":12,"is_preprint":false},{"pmid":"36068004","id":"PMC_36068004","title":"Hsa_circ_0003221 facilitates the malignant development of bladder cancer cells via resulting in the upregulation of DHCR24 by targeting miR-892b.","date":"2022","source":"Investigative and clinical urology","url":"https://pubmed.ncbi.nlm.nih.gov/36068004","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56948,"output_tokens":9765,"usd":0.15866,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20134,"output_tokens":6057,"usd":0.126048,"stage2_stop_reason":"end_turn"},"total_usd":0.284708,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Seladin-1/DHCR24 inhibits caspase-3 activation in response to amyloid-beta toxicity and oxidative stress, protecting cells from apoptotic cell death; endogenous seladin-1 is cleaved to a 40 kDa derivative in a caspase-dependent manner during apoptosis.\",\n      \"method\": \"Functional expression in human neuroglioma H4 cells; caspase-3 activity assays; Western blotting\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional expression with caspase-3 readout, single lab, two orthogonal methods (activity assay + immunoblot)\",\n      \"pmids\": [\"11007892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Following oncogenic and oxidative stress, Seladin-1/DHCR24 binds the p53 amino terminus and displaces the E3 ubiquitin ligase Mdm2 from p53, causing p53 accumulation. Seladin-1 also associates with Mdm2 independently of p53. Ablation of Seladin-1 bypasses Ras-induced senescence and allows cellular transformation; mutants disrupting association with p53 or Mdm2 lose this tumor-suppressive activity.\",\n      \"method\": \"Direct genetic screen; co-immunoprecipitation; loss-of-function (siRNA/ablation) in rodent and human fibroblasts; mutagenesis of interaction interfaces; transformation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, epistasis screen, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"15577914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Seladin-1/DHCR24 is required for normal cholesterol biosynthesis and the formation of cholesterol-rich detergent-resistant membrane domains (DRMs/lipid rafts) in mouse brain. Seladin-1 deficiency displaces beta-secretase (BACE) from DRMs into APP-containing membrane fractions, increasing beta-cleavage of APP and Aβ levels; overexpression reverses this, inducing plasmin activation and reducing BACE processing.\",\n      \"method\": \"DHCR24 knockout mouse brain analysis; cholesterol quantification; DRM fractionation; BACE activity assays; Aβ ELISA; seladin-1 overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO and overexpression with multiple orthogonal biochemical readouts (fractionation, enzyme activity, peptide quantification)\",\n      \"pmids\": [\"16407971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DHCR24 knockout mice die within hours of birth with lethal dermopathy; DHCR24-deficient epidermis lacks cholesterol (replaced by desmosterol) and shows loss of differentiation markers (abnormal keratin 6/14 expression, altered filaggrin/loricrin/involucrin), confirming DHCR24 catalyzes desmosterol→cholesterol conversion essential for epidermal differentiation and barrier function.\",\n      \"method\": \"Targeted gene disruption (DHCR24−/− mice); sterol quantification; immunohistochemistry for keratin/differentiation markers; trans-epidermal water loss measurement; Lucifer yellow permeability assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with multiple orthogonal biochemical and functional readouts\",\n      \"pmids\": [\"16410790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DHCR24−/− mouse embryonic fibroblasts (MEFs) undergo apoptosis upon cholesterol depletion (serum withdrawal) due to disruption of caveolae and impaired insulin receptor (IR)–caveolin-1 co-localization, leading to inactivation of the Akt–Bad survival cascade. Cholesterol repletion rescues Akt activation and prevents apoptosis.\",\n      \"method\": \"DHCR24−/− MEF cultures; subcellular fractionation; immunocytochemistry; phospho-Akt/Bad Western blotting; insulin stimulation rescue experiments\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO cells plus multiple orthogonal mechanistic readouts (fractionation, kinase phosphorylation, rescue experiment)\",\n      \"pmids\": [\"16513830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DHCR24/seladin-1 overexpression confers resistance to oxidative stress in a cholesterol-dependent manner; mutating the reductase activity abolished this protective effect. Under chronic oxidative stress, low DHCR24 levels reduce p53 stability (via elevated p53 ubiquitination/degradation) independently of cholesterol, and DHCR24 ablation prevents neuronal apoptosis in a p53-dependent manner.\",\n      \"method\": \"Neuroblastoma SH-SY5Y cell overexpression; reductase-activity mutants; cholesterol quantification; p53 ubiquitination assays; primary neuron knockdown with p53 rescue\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of catalytic residue, enzymatic activity measurement, p53 ubiquitination assay, and primary neuron KD all in one study\",\n      \"pmids\": [\"17984220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Seladin-1/DHCR24 overexpression increases membrane cholesterol content, reduces accumulation of Aβ42 pre-fibrillar aggregates at the plasma membrane, and prevents amyloid-induced cytosolic Ca2+ rise. Cholesterol depletion (with the specific seladin-1 inhibitor 5,22E-cholestadien-3-ol or methyl-β-cyclodextrin) has the opposite effect.\",\n      \"method\": \"SH-SY5Y neuroblastoma overexpression; PEG-cholesterol supplementation; seladin-1 inhibitor treatment; confocal microscopy of Aβ membrane accumulation; intracellular Ca2+ imaging\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor plus overexpression, single lab, two orthogonal functional readouts\",\n      \"pmids\": [\"18194465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Seladin-1/DHCR24 is a fundamental mediator of estrogen (17β-estradiol, raloxifene, tamoxifen)-induced neuroprotection; siRNA silencing of seladin-1 abolishes estrogen protection against Aβ and oxidative stress toxicity and caspase-3 activation. Half-palindromic estrogen-responsive elements in the seladin-1 promoter confer functional estrogen receptor-alpha-mediated transcriptional activation.\",\n      \"method\": \"siRNA knockdown in fetal neuroepithelial cells; caspase-3 activity assays; luciferase reporter assay with ER-alpha co-transfection; bioinformatic promoter analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with functional caspase readout plus reporter assay validation of ERE, single lab\",\n      \"pmids\": [\"18499757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Seladin-1/DHCR24 is transcriptionally regulated by liver X receptor (LXR): an LXR response element was identified within the second intron of the DHCR24 gene that confers LXR-specific ligand responsiveness; seladin-1/DHCR24 expression is decreased in skin of LXRβ-null mice.\",\n      \"method\": \"Whole-genome ChIP for LXRα occupancy; luciferase reporter assays in HepG2 and HEK293 cells; LXRβ-null mouse gene expression\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identification of binding site plus reporter assay and in vivo KO validation, single lab\",\n      \"pmids\": [\"18815215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Androgen receptor (AR) regulates seladin-1/DHCR24 expression via androgen-responsive element sequences in its promoter; metastatic AR-negative prostate cancer cells have reduced seladin-1/DHCR24 expression and cholesterol; androgen ablation in prostate cancer patients reduces seladin-1/DHCR24 expression.\",\n      \"method\": \"Promoter sequence analysis; AR-positive vs. AR-negative cell line comparison; patient tissue RT-PCR and androgen-ablation treatment cohort\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter element identification plus cell line and patient tissue expression, but no direct AR binding assay in this paper\",\n      \"pmids\": [\"18762779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Down-regulation of seladin-1 in SH-SY5Y cells under apoptotic conditions increases caspase-3 activity, which depletes the BACE1-sorting protein GGA3, leading to increased BACE1 protein levels and activity and enhanced amyloidogenic APP processing and Aβ production. These effects are not seen under normal growth conditions.\",\n      \"method\": \"siRNA knockdown in SH-SY5Y cells; caspase-3 activity assays; GGA3/BACE1 Western blotting; Aβ ELISA; apoptosis induction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple pathway readouts (caspase-3, GGA3, BACE1, Aβ), single lab, mechanistically ordered epistasis\",\n      \"pmids\": [\"19815556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ACTH induces nuclear relocalization of seladin-1 in rat adrenal fasciculata cells (from cytoplasm/cis-Golgi to nucleus), which is blocked by the DHCR24 inhibitor U18666A. In human fasciculata cells, seladin-1 is primarily ER-localized. Inhibition of seladin-1 abolishes ACTH-induced DHEA secretion but not cortisol secretion, and reduces ACTH-induced 11β-hydroxylase expression in rats.\",\n      \"method\": \"Immunofluorescence; subcellular fractionation; U18666A pharmacological inhibition; steroid secretion measurements (ELISA); immunohistochemistry\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation plus pharmacological inhibition with functional steroid secretion readout, single lab\",\n      \"pmids\": [\"19520779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DHCR24 expression is induced by HCV infection in human hepatocytes; siRNA silencing of DHCR24 decreases HCV replication in replicon lines and HCV JFH-1-infected cells; the DHCR24 inhibitor U18666A suppresses HCV replication in vitro and in humanized chimeric mice, with synergistic effect when combined with interferon.\",\n      \"method\": \"siRNA knockdown; U18666A pharmacological inhibition; HCV replicon and JFH-1 infection assays; chimeric mouse model with humanized liver\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA KD and pharmacological inhibition in vitro and in vivo, multiple independent readouts, replicated across cell and animal models\",\n      \"pmids\": [\"21184787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The endogenous oxysterol 24(S),25-epoxycholesterol (24,25EC) rapidly inhibits DHCR24 enzyme activity (not protein levels) to reduce cholesterol synthesis and cause desmosterol accumulation; this effect is independent of DHCR24 protein levels, is specific to certain C-25 oxysterols, and overexpression of DHCR24 blunts this inhibition.\",\n      \"method\": \"Cell-based cholesterol and desmosterol quantification; DHCR24 overexpression; genetic and pharmacological manipulation of 24,25EC levels; multiple mammalian cell lines\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mammalian cell lines tested, genetic and pharmacological manipulation, overexpression rescue, oxysterol specificity analysis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22178193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CAR (constitutive androstane receptor) and PXR transactivate DHCR24 expression; a DR4 motif in the human DHCR24 distal promoter was identified as a binding site for the CAR/RXRα and PXR/RXRα heterodimers, mechanistically linking xenobiotic-responsive nuclear receptors to cholesterol biosynthesis.\",\n      \"method\": \"Reporter gene assays in hepatoma cells; electrophoretic mobility-shift assay (EMSA); mouse liver activation by phenobarbital; CAR activation in cultured human hepatocytes\",\n      \"journal\": \"Toxicology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA binding plus reporter assay plus in vivo mouse and primary human hepatocyte validation, single lab\",\n      \"pmids\": [\"22101211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DHCR24 transcription is regulated primarily through SREBP-2 binding to two cooperative sterol regulatory elements (SREs) in its promoter, assisted by NF-Y binding sites; sterol depletion activates DHCR24 transcription via this SREBP-2 mechanism.\",\n      \"method\": \"Luciferase reporter assays; EMSA; chromatin immunoprecipitation (ChIP); sterol-depletion experiments\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus EMSA plus reporter assay, single lab, three orthogonal methods establishing same mechanism\",\n      \"pmids\": [\"22809995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Full-length DHCR24 localizes to the ER membrane with an N-terminal luminal/C-terminal cytoplasmic orientation (established by fluorescent protease protection assay); the N-terminal transmembrane domain is essential for ER membrane targeting. ER membrane targeting is NOT required for its ROS scavenging activity but the anti-apoptotic function of DHCR24 is associated with its cleavage by caspase.\",\n      \"method\": \"Fluorescent protease protection (FPP) assay; TM-domain deletion mutants; H2DCFDA ROS measurement; confocal fluorescence microscopy; caspase activity assay\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct topology determination by FPP assay plus domain deletion mutagenesis, single lab\",\n      \"pmids\": [\"22010141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DHCR24 promoter transcription is initiated from a single CpG-rich promoter regulated by DNA methylation in some cell types; histone deacetylase inhibition (sodium butyrate) increases DHCR24 expression by recruiting acetylated histones H3/H4 to an enhancer region at −1203/−665 bp, as demonstrated by ChIP.\",\n      \"method\": \"Reporter gene assays; ChIP with anti-acetyl-H3/H4 antibodies; HDAC inhibitor treatment; DNA methylation analysis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus pharmacological HDAC inhibition, single lab\",\n      \"pmids\": [\"20568014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DHCR24 activity is regulated post-translationally by phosphorylation: mutation of residues T110, Y299, and Y507 inhibits DHCR24 enzymatic activity; inhibitors of protein kinase C ablate DHCR24 activity through a different (non-annotated phosphorylation site) mechanism.\",\n      \"method\": \"Site-directed mutagenesis of phosphorylation sites; ectopic human DHCR24 activity assay in CHO-7 cells (with siRNA knockdown of endogenous hamster DHCR24); PKC inhibitor treatment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme activity assay with site-directed mutagenesis plus pharmacological inhibition, rigorous system to isolate human DHCR24 activity\",\n      \"pmids\": [\"24363437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DHCR24 overexpression protects neuronal N2A cells from ER stress-induced apoptosis by reducing caspase-12 activity, diminishing ER stress markers (Bip, CHOP), attenuating JNK/p38 activation, decreasing intracellular ROS, and promoting caveolae formation with improved caveolin-1/IGF1R co-localization.\",\n      \"method\": \"Adenoviral DHCR24 overexpression in N2A cells; tunicamycin-induced ER stress; caspase-12 assay; Western blotting for ER stress markers; H2DCFDA ROS assay; confocal microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct overexpression with multiple orthogonal mechanistic readouts, single lab\",\n      \"pmids\": [\"24489783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DHCR24 (seladin-1) maintains lipid raft integrity in the ischemic brain; genetic heterozygous deletion (Dhcr24+/−) or pharmacological inhibition enlarges infarct volume, increases neuroinflammatory mediators, and reduces the association of glutamate transporter EAAT2 with lipid rafts, impairing glutamate uptake.\",\n      \"method\": \"Dhcr24+/− mice with middle cerebral artery occlusion; U18666A pharmacological inhibition; infarct volume measurement; lipid raft fractionation Western blot; [3H]-glutamate uptake assay in astrocyte cultures\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and pharmacological inhibition, in vivo infarct quantification, fractionation assay, and functional transport assay; multiple orthogonal methods\",\n      \"pmids\": [\"26628388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DHCR24 and DHCR7 (7-dehydrocholesterol reductase) physically interact by co-immunoprecipitation; DHCR24 knockdown ablates DHCR7 enzymatic activity, and DHCR24 overexpression (functional form only) enhances DHCR7 activity, indicating a functional cholesterol 'metabolon' with substrate channeling.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown of DHCR24; DHCR7 enzymatic activity assay; overexpression of functional vs. non-functional DHCR24\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional interaction established by Co-IP and enzyme activity assay with mutagenesis control, single lab\",\n      \"pmids\": [\"25637936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Insulin induces DHCR24 expression through STAT3, which directly binds to the DHCR24 promoter (demonstrated by ChIP-PCR and luciferase assay); silencing DHCR24 inhibits endometrial cancer cell metastasis and upregulates progesterone receptor (PGR) expression.\",\n      \"method\": \"ChIP-PCR; luciferase reporter assay; siRNA knockdown; cell migration assays; PGR Western blotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR plus luciferase reporter establishing STAT3 binding to DHCR24 promoter, plus functional KD assay, single lab\",\n      \"pmids\": [\"28112250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DHCR24 overexpression protects neurons against LPS/IFN-γ-induced neuroinflammatory death in co-cultures and increases neuroligin-1 levels, dendritic spine density, and the proportion of mushroom spines; in vivo, DHCR24 overexpression in striatum reduces ischemic lesion size in a mouse transient focal ischemia model.\",\n      \"method\": \"Neuronal–microglial co-culture with LPS/IFN-γ; adeno-associated virus DHCR24 overexpression in vivo; MRI infarct measurement; dendritic spine morphology analysis; Western blotting for neuroligin-1\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro co-culture plus in vivo gene delivery with functional outcome measures, single lab\",\n      \"pmids\": [\"29115990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Dhcr24 overexpression protects against dilated cardiomyopathy (DCM) in cTnTR141W transgenic mice by activating the PI3K/Akt/HKII pathway and reducing Bax translocation, cytochrome c release, and caspase-9/caspase-3 activation. PI3K inhibition completely removes the anti-apoptotic effect; HKII inhibition only partially reduces it.\",\n      \"method\": \"Heart-specific transgenic Dhcr24 overexpression in DCM mice; Western blotting for PI3K/Akt/HKII pathway; TUNEL assay; echocardiography; PI3K and HKII inhibitors in H9c2 cells\",\n      \"journal\": \"Animal models and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic overexpression with pathway epistasis via inhibitors, multiple apoptosis readouts, single lab\",\n      \"pmids\": [\"30891546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-124 directly targets Dhcr24 in cardiomyocytes; miR-124 overexpression increases cardiomyocyte apoptosis, which is mediated through downregulation of Dhcr24; miR-124 inhibition attenuates cell death; the miR-124–Dhcr24 axis regulates oxidative stress- and hypoxia-induced cardiomyocyte apoptosis and myocardial infarction in vivo.\",\n      \"method\": \"miR-124 overexpression/inhibition in cardiomyocytes; 3'UTR luciferase reporter (implied by target identification); in vivo intra-myocardial agomiR/antagomiR injection; apoptosis assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — target validation plus in vivo miRNA manipulation, functional apoptosis readout; miRNA targeting assay details not fully described in abstract\",\n      \"pmids\": [\"31100313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genkwadaphnin (GD) suppresses DHCR24 expression and enzymatic activity, thereby inhibiting DHCR24-mediated cholesterol biosynthesis and lipid raft formation, which reduces HCC cell invasion and migration in vitro and tumor growth in vivo.\",\n      \"method\": \"DHCR24 siRNA knockdown; GD pharmacological inhibition; cholesterol level measurement; lipid raft structural assay; HCC xenograft in BALB/c nude mice; microarray gene expression\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological inhibition with multiple functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"32958824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DHCR24 overexpression in BV-2 microglia treated with Aβ25-35 reverses M1 polarization toward M2 phenotype and activates the Akt/GSK3β signaling pathway; co-treatment with the Akt inhibitor MK2206 reverses the effect of DHCR24, placing DHCR24 upstream of Akt/GSK3β in microglial inflammatory regulation.\",\n      \"method\": \"Lentiviral DHCR24 overexpression in BV-2 cells; Western blotting for P-Akt and P-GSK3β; cytokine (iNOS, IL-1β, TNF-α, arginase-1, IL-4, TGF-β) measurement; Akt inhibitor epistasis\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression plus pharmacological epistasis, single lab, multiple polarization markers\",\n      \"pmids\": [\"32950573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DHCR24 knockdown in SH-SY5Y cells reduces plasma membrane cholesterol and caveolin-1, disrupts lipid rafts/caveolae, decreases PI3-K/Akt signaling (reduced p-Akt at Thr308 and Ser473), activates GSK3β, and activates mTOR, leading to tau hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396 and inhibition of autophagy; DHCR24 knock-in reverses all these effects.\",\n      \"method\": \"siRNA knockdown and overexpression (knock-in); Western blotting for cholesterol, caveolin-1, p-Akt, p-GSK3β, p-mTOR, LC3-II/I, p62; phospho-tau Western blotting; autophagosome counting\",\n      \"journal\": \"Frontiers in aging neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (KD and KI) with multiple ordered pathway readouts, single lab\",\n      \"pmids\": [\"33967735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DHCR24 knockdown in SH-SY5Y cells decreases plasma membrane cholesterol and caveolin-1, inhibiting PP2A activity (via increased p-PP2Ac at Y307) and activating GSK3β (via increased p-GSK3β at Y216), leading to tau hyperphosphorylation at multiple sites (Thr181, Thr231, Ser262, Ser396, Ser422); PP2A activator D-erythro-Sphingosine reverses the tau hyperphosphorylation induced by DHCR24 knockdown.\",\n      \"method\": \"siRNA knockdown and DHCR24 overexpression; Western blotting for PP2A activity markers, GSK3β, and phospho-tau; Filipin III cholesterol staining; PP2A activator rescue experiment\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation plus enzymatic rescue epistasis, single lab, multiple pathway nodes measured\",\n      \"pmids\": [\"33710538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOX9 directly transcriptionally activates DHCR24 expression in diffuse large B-cell lymphomas (DLBCL) bearing IGH-BCL2 translocations, as shown by whole-transcriptome analysis and ChIP-seq; enforced DHCR24 expression rescues cell proliferation after SOX9 knockdown; DHCR24 mediates SOX9-driven cholesterol synthesis and lymphomagenesis.\",\n      \"method\": \"Whole-transcriptome analysis; ChIP-seq; SOX9 siRNA knockdown; DHCR24 forced expression rescue; xenograft tumor model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq direct binding evidence plus epistatic rescue experiment in vitro and in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"34624089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF3 directly regulates DHCR24 expression in colorectal cancer; SRSF3 silencing suppresses DHCR24, and the SRSF3 inhibitor SFI003 drives apoptosis via the SRSF3/DHCR24/ROS axis; elevated ROS upon DHCR24 reduction mediates the anticancer effect.\",\n      \"method\": \"SRSF3 siRNA knockdown; SFI003 pharmacological inhibition; DHCR24 expression measurement; ROS quantification; in vitro and in vivo xenograft assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological epistasis with functional ROS readout in vitro and in vivo, single lab\",\n      \"pmids\": [\"35501301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DHCR24 knockdown in C8D1A astrocytes decreases cholesterol in plasma membrane and intracellular organelles, reduces caveola-associated protein cavin1, disrupts lipid rafts/caveolae, and activates the caveolae-dependent Ras/MEK/ERK signaling pathway, leading to tau hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, Ser396; DHCR24 overexpression prevents ERK overactivation and tau hyperphosphorylation.\",\n      \"method\": \"siRNA knockdown and overexpression in C8D1A astrocytes; Filipin III staining; Western blotting for cavin1, Ras/MEK/ERK pathway, phospho-tau; cholesterol quantification\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation in astrocytes with lipid raft disruption and signaling pathway readouts, single lab\",\n      \"pmids\": [\"35804281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-7 post-transcriptionally suppresses DHCR24 expression by targeting its 3'UTR, thereby blocking the last steps of cholesterol biosynthesis; intracranial AAV-delivered miR-7 reduces DHCR24 in mouse brain. Cholesterol reciprocally regulates miR-7 levels through SREBP2-mediated transcription, establishing a feedback loop.\",\n      \"method\": \"In vitro miR-7 overexpression; AAV intracranial delivery in mice; DHCR24 expression measurement; SREBP2 ChIP on miR-7 host gene promoter; Niemann Pick C1 mouse model and fatty liver model\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo miRNA manipulation plus SREBP2 ChIP evidence for feedback regulation, single lab\",\n      \"pmids\": [\"37086967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pharmacological inhibition of DHCR24 by SH42 increases desmosterol in liver and plasma, activates LXRα, reduces hepatic lipid content and steatosis, decreases Kupffer cell activation and monocyte infiltration, and reduces liver collagen and ALT levels; LXRα deficiency completely abolishes all beneficial effects of SH42, placing DHCR24 upstream of LXRα in NAFLD/NASH regulation.\",\n      \"method\": \"APOE*3-Leiden.CETP mouse model; SH42 pharmacological inhibition; desmosterol quantification; flow cytometry; LXRα knockout mice; liver histology; collagen/ALT measurements\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological inhibition combined with LXRα KO genetic epistasis in a validated translational mouse model, multiple orthogonal functional readouts\",\n      \"pmids\": [\"37357756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AAV-mediated DHCR24 overexpression in hippocampus of 5xFAD mice increases cholesterol, reverses cognitive impairment, reduces amyloid-β deposition, synaptic injury, autophagy dysfunction, reactive astrocytosis, microglial phagocytosis abnormalities, and apoptosis.\",\n      \"method\": \"AAV hippocampal delivery in 5xFAD mice; cholesterol quantification; behavioral tests; immunohistochemistry for Aβ, synaptic, autophagy, and apoptotic markers\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene delivery with multiple outcome measures in a validated AD model, single lab\",\n      \"pmids\": [\"37344916\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DHCR24 (seladin-1) is an FAD-dependent oxidoreductase anchored to the ER membrane (N-terminal luminal, C-terminal cytoplasmic) that catalyzes the terminal conversion of desmosterol to cholesterol; its enzymatic activity—regulated transcriptionally by SREBP-2, LXR, CAR/PXR, AR, ER-alpha, and miR-7/miR-124, and post-translationally by phosphorylation at T110/Y299/Y507 and by oxysterol 24,25-epoxycholesterol—controls membrane cholesterol content and lipid raft/caveolae integrity, which in turn modulates multiple downstream signaling cascades (PI3K/Akt/Bad, Akt/GSK3β/mTOR, PP2A, Ras/MEK/ERK, EAAT2-mediated glutamate uptake); independently of cholesterol synthesis, DHCR24 stabilizes p53 by binding its N-terminus and displacing Mdm2, thereby mediating the cellular response to oncogenic and oxidative stress, and inhibits caspase-3 to confer neuroprotection against Aβ toxicity, ER stress, and neuroinflammation; DHCR24 additionally serves as an obligate host factor for HCV replication and functions upstream of LXRα to regulate hepatic lipid homeostasis and inflammation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DHCR24 (seladin-1) is an FAD-dependent oxidoreductase of the ER membrane that catalyzes the terminal step of cholesterol biosynthesis, reducing desmosterol to cholesterol, and through this activity governs membrane cholesterol content and the integrity of cholesterol-rich detergent-resistant membrane domains (lipid rafts/caveolae) that organize downstream signaling [#3, #2, #13]. The enzyme adopts an N-terminal-luminal/C-terminal-cytoplasmic ER topology, with its N-terminal transmembrane domain required for ER targeting; its catalytic activity depends on phosphorylatable residues T110, Y299, and Y507 and is acutely inhibited by the endogenous oxysterol 24(S),25-epoxycholesterol independently of protein level [#16, #18, #13]. In vivo, DHCR24 loss is neonatally lethal with desmosterol-for-cholesterol replacement that disrupts epidermal differentiation and barrier function, establishing the enzyme's non-redundant role in cholesterol production [#3]. By maintaining raft/caveolae integrity, DHCR24 sustains caveolin-1-dependent receptor signaling and survival cascades—including insulin/IGF1R-Akt-Bad, Akt/GSK3\\u03b2/mTOR, PP2A, and Ras/MEK/ERK—such that its depletion disrupts these axes and drives tau hyperphosphorylation, while it also partners physically with DHCR7 in a cholesterol-synthesis metabolon [#4, #28, #29, #32, #21]. Independently of cholesterol synthesis, DHCR24 binds the p53 N-terminus and displaces Mdm2 to stabilize p53, mediating responses to oncogenic and oxidative stress, and confers anti-apoptotic neuroprotection against amyloid-\\u03b2, ER stress, and neuroinflammation in part by limiting caspase activation [#1, #5, #19]. Its expression is controlled by a broad transcriptional network—SREBP-2, LXR, CAR/PXR, AR, ER-alpha, STAT3, SOX9—and by the microRNAs miR-7 and miR-124 [#15, #8, #14, #9, #7, #22, #30, #33, #25]. DHCR24 functions upstream of LXR\\u03b1 in hepatic lipid and inflammatory homeostasis and serves as a required host factor for HCV replication [#34, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the first cellular function of seladin-1 as an anti-apoptotic neuroprotective factor, framing the gene beyond a metabolic enzyme.\",\n      \"evidence\": \"functional expression in H4 neuroglioma cells with caspase-3 activity assays and immunoblot\",\n      \"pmids\": [\"11007892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking seladin-1 to caspase-3 inhibition not defined\", \"Did not establish enzymatic basis or substrate\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed a cholesterol-independent tumor-suppressive mechanism: DHCR24 stabilizes p53 by binding its N-terminus and displacing Mdm2.\",\n      \"evidence\": \"genetic screen, reciprocal co-IP, interface mutagenesis, and transformation assays in fibroblasts\",\n      \"pmids\": [\"15577914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of p53/Mdm2 interface binding not resolved\", \"Relationship between this moonlighting function and the reductase activity unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined DHCR24 as the enzyme catalyzing desmosterol\\u2192cholesterol conversion essential in vivo, and linked its loss to lipid raft disruption and amyloidogenic APP processing.\",\n      \"evidence\": \"DHCR24 knockout mouse brain and epidermis analysis with sterol quantification, DRM fractionation, BACE assays, and differentiation markers\",\n      \"pmids\": [\"16407971\", \"16410790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme kinetics and cofactor requirements not characterized here\", \"Tissue-specific consequences beyond brain and skin not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected DHCR24-dependent cholesterol to caveolae-organized insulin receptor/Akt-Bad survival signaling.\",\n      \"evidence\": \"DHCR24\\u2212/\\u2212 MEFs with fractionation, phospho-Akt/Bad immunoblot, and cholesterol-repletion rescue\",\n      \"pmids\": [\"16513830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between cholesterol and IR-caveolin co-localization not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Distinguished two protective modes\\u2014cholesterol-dependent oxidative-stress resistance and cholesterol-independent p53 stabilization\\u2014using catalytic mutants.\",\n      \"evidence\": \"SH-SY5Y overexpression with reductase-activity mutants, p53 ubiquitination assays, and primary neuron knockdown with p53 rescue\",\n      \"pmids\": [\"17984220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How chronic stress switches between the two modes not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the transcriptional regulators of DHCR24, placing cholesterol synthesis under hormonal (ER-alpha, AR) and oxysterol (LXR) control.\",\n      \"evidence\": \"luciferase reporters, ChIP, promoter element analysis, and LXR\\u03b2-null/cell line expression\",\n      \"pmids\": [\"18499757\", \"18815215\", \"18762779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AR binding not assayed in some studies\", \"Tissue-specific contribution of each regulator not quantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed DHCR24-driven membrane cholesterol limits amyloid-\\u03b2 plasma-membrane accumulation and calcium dysregulation.\",\n      \"evidence\": \"SH-SY5Y overexpression and seladin-1 inhibitor treatment with confocal A\\u03b2 imaging and Ca2+ imaging\",\n      \"pmids\": [\"18194465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibitor specificity not fully controlled\", \"Direct membrane interaction mechanism not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Ordered the caspase-3/GGA3/BACE1 axis downstream of seladin-1 loss under apoptotic conditions, linking apoptosis to amyloidogenesis.\",\n      \"evidence\": \"siRNA knockdown in SH-SY5Y with caspase-3 assays, GGA3/BACE1 immunoblot, and A\\u03b2 ELISA\",\n      \"pmids\": [\"19815556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect confined to apoptotic conditions; physiological relevance unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Documented ACTH-induced nuclear relocalization of seladin-1 and a steroidogenic role in adrenal DHEA secretion.\",\n      \"evidence\": \"immunofluorescence, fractionation, U18666A inhibition, and steroid ELISA in rat and human fasciculata cells\",\n      \"pmids\": [\"19520779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of nuclear relocalization not established\", \"Species differences in localization unexplained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified DHCR24 as an obligate host factor for HCV replication and a druggable antiviral target.\",\n      \"evidence\": \"siRNA knockdown and U18666A inhibition in replicon/JFH-1 systems and humanized chimeric mice\",\n      \"pmids\": [\"21184787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular step in HCV replication requiring DHCR24 not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established post-translational and additional transcriptional control of DHCR24: acute oxysterol inhibition of activity and CAR/PXR transactivation.\",\n      \"evidence\": \"cell-based sterol quantification with overexpression rescue; reporter assays, EMSA, and in vivo phenobarbital induction\",\n      \"pmids\": [\"22178193\", \"22101211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of 24,25EC inhibition of the enzyme not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved DHCR24 transcriptional, epigenetic, and topological regulation, establishing SREBP-2/NF-Y control, methylation/HDAC sensitivity, and ER membrane orientation.\",\n      \"evidence\": \"reporter assays, EMSA, ChIP, methylation analysis, and fluorescent protease protection topology assay\",\n      \"pmids\": [\"22809995\", \"20568014\", \"22010141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ER topology for catalysis not defined\", \"ER targeting dispensable for ROS scavenging—alternate localization not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified specific phosphorylation sites (T110, Y299, Y507) and PKC-dependent regulation as post-translational controls of reductase activity.\",\n      \"evidence\": \"site-directed mutagenesis with ectopic human DHCR24 activity assay in CHO-7 cells and PKC inhibitor treatment\",\n      \"pmids\": [\"24363437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Responsible kinases not identified\", \"Phosphorylation stoichiometry under physiological signaling unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a DHCR24-DHCR7 cholesterol metabolon and a brain-protective raft function maintaining EAAT2-mediated glutamate uptake.\",\n      \"evidence\": \"co-IP and reciprocal enzyme activity assays; Dhcr24+/\\u2212 MCAO mice with raft fractionation and glutamate uptake assays\",\n      \"pmids\": [\"25637936\", \"26628388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate channeling between DHCR24 and DHCR7 not visualized\", \"Stoichiometry of the metabolon unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended DHCR24 transcriptional control to insulin/STAT3 and linked it to cancer cell behavior.\",\n      \"evidence\": \"ChIP-PCR, luciferase reporter, siRNA knockdown, and migration assays in endometrial cancer cells\",\n      \"pmids\": [\"28112250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether metastatic effect depends on cholesterol synthesis vs. moonlighting function not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped DHCR24 cardioprotection through PI3K/Akt/HKII anti-apoptotic signaling in dilated cardiomyopathy.\",\n      \"evidence\": \"heart-specific transgenic overexpression in DCM mice with pathway epistasis by PI3K/HKII inhibitors and apoptosis readouts\",\n      \"pmids\": [\"30891546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protection requires cholesterol synthesis not tested with catalytic mutants\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the miR-124\\u2013Dhcr24 axis controlling cardiomyocyte apoptosis and infarction.\",\n      \"evidence\": \"miR-124 gain/loss in cardiomyocytes, 3'UTR reporter, and in vivo agomiR/antagomiR injection with apoptosis assays\",\n      \"pmids\": [\"31100313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"miRNA targeting assay details limited\", \"Direct 3'UTR binding only implied\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Consolidated DHCR24 as an upstream regulator of microglial polarization (Akt/GSK3\\u03b2) and as a cholesterol/raft-dependent driver of HCC invasion.\",\n      \"evidence\": \"lentiviral/siRNA manipulation with Akt-inhibitor epistasis in BV-2 cells; siRNA and genkwadaphnin inhibition with raft and xenograft assays in HCC\",\n      \"pmids\": [\"32950573\", \"32958824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from DHCR24 to Akt activation not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the cholesterol/caveolae \\u2192 Akt-GSK3\\u03b2-mTOR and PP2A signaling cascades whose disruption by DHCR24 loss drives tau hyperphosphorylation and impaired autophagy.\",\n      \"evidence\": \"bidirectional knockdown/knock-in in SH-SY5Y with phospho-tau, PP2A/GSK3\\u03b2 markers, autophagy readouts, and enzymatic rescue\",\n      \"pmids\": [\"33967735\", \"33710538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal hierarchy among Akt, PP2A, and mTOR nodes not fully ordered\", \"In vivo relevance to tauopathy not tested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended raft-dependent signaling to astrocytic Ras/MEK/ERK-driven tau pathology and identified SOX9 and SRSF3 as cancer-context regulators of DHCR24.\",\n      \"evidence\": \"bidirectional manipulation in astrocytes; ChIP-seq/rescue (SOX9) and siRNA/SFI003 ROS-axis assays (SRSF3) with xenografts\",\n      \"pmids\": [\"35804281\", \"34624089\", \"35501301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type specificity of each upstream regulator not generalized\", \"Whether ROS effects are downstream of cholesterol loss vs. moonlighting not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established DHCR24 as upstream of LXR\\u03b1 in hepatic lipid/inflammation control, identified a miR-7\\u2013cholesterol feedback loop, and demonstrated in vivo neuroprotection in an AD model.\",\n      \"evidence\": \"SH42 inhibition with LXR\\u03b1-KO epistasis in APOE*3-Leiden.CETP mice; miR-7 manipulation with SREBP2 ChIP; AAV DHCR24 overexpression in 5xFAD mice\",\n      \"pmids\": [\"37357756\", \"37086967\", \"37344916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which desmosterol activates LXR\\u03b1 in vivo not fully dissected\", \"Translational dosing/safety of DHCR24 modulation unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DHCR24's catalytic (cholesterol-synthesis) and moonlighting (p53-stabilizing, anti-caspase) functions are coordinated, and which is required in each disease context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the enzyme or its p53/Mdm2 interface\", \"No clean separation-of-function genetics across tissues\", \"Kinases and signals controlling phosphorylation-dependent activity unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 13, 18, 21]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [16, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 28, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 13, 34]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 5, 19, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 28, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 30]}\n    ],\n    \"complexes\": [\"DHCR24-DHCR7 cholesterol metabolon\"],\n    \"partners\": [\"TP53\", \"MDM2\", \"DHCR7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}