{"gene":"DHCR7","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2015,"finding":"DHCR7 physically interacts with DHCR24 (24-dehydrocholesterol reductase): the two terminal cholesterol synthesis enzymes co-immunoprecipitate, and siRNA knockdown of DHCR24 ablates DHCR7 activity, while overexpression of functional DHCR24 enhances DHCR7 activity. This suggests a cholesterol 'metabolon' with substrate channeling.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression activity assays","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional siRNA and overexpression rescue experiments in a single focused study; multiple orthogonal methods","pmids":["25637936"],"is_preprint":false},{"year":2016,"finding":"Phosphorylation regulates DHCR7 enzymatic activity: pharmacological inhibition of AMP-activated protein kinase or protein kinase A significantly decreases DHCR7 activity, and mutation of a known phosphorylated residue (S14) also decreases activity, indicating phosphorylation is required for full catalytic function.","method":"Pharmacological kinase inhibitors, site-directed mutagenesis (S14 mutant), enzymatic activity assay in cells","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — mutagenesis plus pharmacological inhibition in a single lab study; no independent replication","pmids":["27520299"],"is_preprint":false},{"year":2014,"finding":"The human DHCR7 promoter is transcriptionally regulated by SREBP-2 via two binding sites (at −155 and −55) and an NF-Y cofactor site (at −136). The two SREs cooperate synergistically to activate DHCR7 transcription in response to sterol depletion.","method":"Promoter-reporter assays, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis of SRE elements","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with mutagenesis and EMSA, single lab but multiple orthogonal methods","pmids":["25048193"],"is_preprint":false},{"year":2009,"finding":"Wild-type DHCR7 (and the related sterol reductase TM7SF2) expression in human cell lines causes massive expansion of the endoplasmic reticulum and perinuclear space, including separation of inner and outer nuclear membranes, loss of nuclear pore complexes, and formation of cytoplasmic vacuoles — demonstrating that DHCR7 overexpression can severely disrupt ER and nuclear envelope organization.","method":"Live cell imaging, electron microscopy, overexpression of wild-type DHCR7 in multiple human cell lines","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging with EM validation in multiple cell lines, single lab","pmids":["19940018"],"is_preprint":false},{"year":2021,"finding":"Rat DHCR7 can reduce 20S(OH)7DHC and 27(OH)7DHC as substrates (removing the C7–C8 double bond), but lumisterol (L3), 8-DHC, and 7-dehydropregnenolone are not substrates — 8-DHC and 20S(OH)L3 act as inhibitors. Vitamin D3 and its hydroxy-derivatives do not inhibit DHCR7. This defines the substrate specificity and inhibitor profile of the active site.","method":"In vitro enzyme assay with rat liver microsomes, ergosterol-to-brassicasterol conversion inhibition screen, direct substrate testing by LC-MS product detection","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple substrates and mutagenesis-independent active-site screening; rigorous product identification by mass spectrometry","pmids":["34098080"],"is_preprint":false},{"year":2004,"finding":"DHCR7 enzymatic activity (measured by ergosterol-to-brassicasterol conversion) is significantly reduced in fibroblasts, amniocytes, and chorionic villi from SLOS patients compared to carriers and controls, establishing a quantitative functional threshold (below ~8% conversion causes disease). Enzyme activity does not correlate with clinical severity score or plasma sterol ratios.","method":"Cell-based enzymatic activity assay (ergosterol conversion) in multiple primary cell types from patients, carriers, and controls","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — activity measured across multiple cell types with well-defined patient genotypes; single lab","pmids":["15464432"],"is_preprint":false},{"year":2007,"finding":"Replenishment of 7-dehydrocholesterol (7-DHC) into cholesterol-depleted native hippocampal membranes does not restore ligand binding activity of the serotonin1A receptor, despite recovering overall membrane order — demonstrating that the structural difference introduced by DHCR7 substrate accumulation (the C7–C8 double bond) is functionally distinct from cholesterol for receptor function.","method":"Cholesterol depletion/replenishment in hippocampal membranes, radioligand binding assay, membrane order measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — replicated independently in two separate papers (PMID 17493586 and 17904101) using both native and solubilized membrane preparations","pmids":["17493586","17904101"],"is_preprint":false},{"year":2022,"finding":"Zika virus non-structural protein NS4B physically interacts with DHCR7 and induces its expression. Upregulated DHCR7 in turn inhibits TBK1 and IRF3 phosphorylation, reducing IFN-β and interferon-stimulated gene production and thereby facilitating viral immune evasion. Blocking DHCR7 suppresses ZIKV infection.","method":"Co-immunoprecipitation (NS4B–DHCR7 interaction), overexpression/knockdown with DHCR7, phosphorylation assays for TBK1/IRF3, IFN-β and ISG reporter assays","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional signaling assays plus knockdown rescue, single lab","pmids":["36182074"],"is_preprint":false},{"year":2020,"finding":"Disruption of Dhcr7 in osteoblasts alters intracellular cholesterol status, causing abnormalities in primary cilia number and length through dysregulated ciliary vesicle fusion, which in turn impairs WNT/β-catenin and hedgehog signaling and leads to defective osteoblast differentiation and craniofacial bone formation. Simvastatin treatment rescues ciliogenesis and osteogenesis defects.","method":"Conditional Dhcr7 knockout mouse model, primary cilia imaging, ciliary vesicle fusion assay, WNT/hedgehog pathway reporters, simvastatin rescue experiment","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific cellular phenotypes, pathway analysis by signaling reporters, and pharmacological rescue; multiple orthogonal methods in a single rigorous study","pmids":["31934493"],"is_preprint":false},{"year":2007,"finding":"Liver-specific transgenic restoration of DHCR7 expression in Dhcr7-null mice normalizes cholesterol levels in liver and lung (80–90% of normal) and rescues late gestational lung sacculation defects, but does not rescue brain cholesterol deficiency or neonatal lethality, demonstrating that CNS-specific DHCR7 function is essential for survival.","method":"Liver-specific transgenic complementation (ApoE promoter-driven DHCR7), tissue cholesterol biochemistry, survival analysis in Dhcr7-null mice","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via tissue-selective transgenic rescue with biochemical validation; rigorous tissue-specific design establishing tissue autonomy","pmids":["17408495"],"is_preprint":false},{"year":2006,"finding":"In Dhcr7-knockout fetuses (which cannot convert 7-DHC to cholesterol), brain cholesterol is almost entirely of fetal/local origin from ~E11–12 onward (90% at birth), whereas peripheral organ cholesterol is substantially maternal in origin early in gestation, transitioning to predominantly fetal synthesis by birth. This establishes that the blood-brain barrier demarcates autonomous fetal brain cholesterol synthesis.","method":"Isotopic tracing using Dhcr7 knockout fetuses in heterozygous mothers; sterol profiling by GC-MS across gestational ages in brain, liver, and lung","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — elegant genetic model with rigorous biochemical sterol quantification; definitive origin-tracing experiment","pmids":["16651660"],"is_preprint":false},{"year":2024,"finding":"DHCR7 promotes cervical cancer lymph node metastasis via two mechanisms: (1) upregulating KANK4 and subsequently activating PI3K/AKT signaling, and (2) promoting secretion of VEGF-C to drive lymphangiogenesis. Both mechanisms require intact cholesterol reprogramming by DHCR7. DHCR7 inhibitors AY9944 and tamoxifen significantly inhibited lymph node metastasis in vivo.","method":"Gain- and loss-of-function experiments in vitro, xenograft mouse models in vivo, VEGF-C ELISA, PI3K/AKT pathway Western blotting, KANK4 interaction studies","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods in a single lab study","pmids":["38211648"],"is_preprint":false},{"year":2024,"finding":"Sevoflurane-induced autophagic degradation of DHCR7 causes accumulation of its substrate 7-DHC, which activates AKT3 and downstream IRF3-driven cytokine transcription (IL-6, TNF-α), leading to hippocampal neuroinflammation. Autophagy inhibitor 3-MA reverses DHCR7 degradation, AKT3 phosphorylation, IRF3 activation, and 7-DHC accumulation.","method":"Autophagy inhibition (3-MA) in neonatal mouse model and in vitro, DHCR7 protein quantification, 7-DHC measurement, AKT3 and IRF3 phosphorylation assays, cytokine measurements","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological intervention with matched biochemical readouts in both in vivo and in vitro systems; single lab","pmids":["38901498"],"is_preprint":false},{"year":2016,"finding":"Inhibition of DHCR7 (the enzyme converting 7-DHC to cholesterol) in palatal shelf explants by RNAi causes failure of palatal fusion, accompanied by reduced expression of Shh and Bmp2. Exogenous cholesterol supplementation restores Shh and Bmp2 expression without affecting Dhcr7 silencing, placing DHCR7 upstream of SHH and BMP2 in palatogenesis.","method":"RNAi knockdown in palatal shelf culture, scanning electron microscopy, RT-PCR/Western blot for Shh and Bmp2, cholesterol rescue experiment","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with cholesterol rescue establishing pathway position; single lab, ex vivo culture system","pmids":["27066502"],"is_preprint":false},{"year":2026,"finding":"RTN3 (reticulon 3) binds to DHCR7 and promotes its ubiquitination; downregulation of RTN3 stabilizes DHCR7, elevates cholesterol levels, and activates the EGFR/ERK pathway to promote thyroid cancer progression. Simvastatin (HMG-CoA reductase inhibitor) rescues the effects of RTN3 downregulation.","method":"Co-immunoprecipitation (RTN3–DHCR7), ubiquitination assay, knockdown/overexpression with pathway Western blotting, simvastatin rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional rescue; single lab","pmids":["41813657"],"is_preprint":false},{"year":2024,"finding":"In dhcr7-deficient zebrafish, loss of DHCR7 function causes increased lysosomes and attenuated autophagy in axons, linking disrupted autophagy-related neuronal homeostasis to compromised myelination, synaptic anomalies, and neurotransmitter imbalances, as well as microcephaly and ADHD-like behavior.","method":"Dhcr7 knockout zebrafish (dhcr7-/-), lysosome and autophagy marker quantification, behavioral assays, myelination and synapse imaging","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific cellular and behavioral phenotypes; single lab study in zebrafish","pmids":["38626530"],"is_preprint":false},{"year":2001,"finding":"Expression studies of DHCR7 missense mutations identified in SLOS patients demonstrated decreased protein stability for all analyzed missense mutations. Clustering of mutations in three protein domains (transmembrane domain, fourth cytoplasmic loop, C-terminus) was established, with null and 4L mutations causing severe phenotype and TM/CT mutations causing mild phenotype, defining structure–function relationships.","method":"Mutation expression studies in cell lines, protein stability assays, clinical genotype-phenotype correlation across patient cohorts","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression studies with protein stability readout across multiple mutations; replicated in multiple patient cohorts","pmids":["11241839"],"is_preprint":false},{"year":2026,"finding":"DHCR7 knockdown or treatment with tamoxifen in AML cells reduces intracellular cholesterol, causes 7-DHC accumulation, induces endoplasmic reticulum stress, triggers apoptosis, and suppresses leukaemia progression in NSG mouse models. Mechanistically, DHCR7 activates the IL-6/JAK2/STAT3 signalling axis in AML.","method":"siRNA knockdown and tamoxifen treatment in AML cell lines, cholesterol and 7-DHC measurement, ER stress markers, JAK2/STAT3 phosphorylation assays, NSG mouse xenograft model","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo methods; IL6/JAK2/STAT3 pathway mechanistic investigation; single lab","pmids":["41608869"],"is_preprint":false}],"current_model":"DHCR7 is an endoplasmic reticulum-resident sterol reductase that catalyzes the final step of cholesterol biosynthesis (conversion of 7-dehydrocholesterol to cholesterol) in the Kandutsch-Russell pathway; its activity is regulated by SREBP-2-driven transcription (via cooperative SREs at −155 and −55 in the promoter), by phosphorylation at residue S14 (via AMPK and PKA), and by a physical and functional interaction with the terminal Bloch-pathway enzyme DHCR24, forming a putative cholesterol metabolon; substrate specificity studies show it acts on 7-DHC and selected hydroxy-derivatives but not lumisterol or vitamin D3; loss of DHCR7 function causes 7-DHC accumulation that impairs serotonin1A receptor function, disrupts primary ciliogenesis and downstream WNT/hedgehog signaling in osteoblasts, triggers autophagic–AKT3–IRF3 neuroinflammatory signaling, and compromises axonal autophagy in neurons, while tissue-selective rescue experiments establish that brain-autonomous DHCR7 activity is essential for neonatal survival."},"narrative":{"mechanistic_narrative":"DHCR7 is an endoplasmic reticulum sterol reductase that catalyzes the final step of cholesterol biosynthesis, reducing the C7–C8 double bond to convert 7-dehydrocholesterol (7-DHC) to cholesterol [PMID:34098080, PMID:15464432]. Substrate-specificity studies define a constrained active site that reduces 7-DHC and selected hydroxy-7DHC derivatives such as 20S(OH)7DHC and 27(OH)7DHC, while lumisterol, 8-DHC, and 7-dehydropregnenolone are not substrates and several of these instead act as inhibitors [PMID:34098080]. The enzyme operates as part of a terminal cholesterol-synthesis unit through physical and functional interaction with DHCR24, with DHCR24 required for full DHCR7 activity, consistent with a substrate-channeling metabolon [PMID:25637936]. DHCR7 output is controlled at multiple levels: transcriptionally by SREBP-2 acting through two cooperative sterol response elements and an NF-Y site in the promoter upon sterol depletion [PMID:25048193], post-translationally by phosphorylation at S14 downstream of AMPK and PKA [PMID:27520299], and by protein stability, as RTN3 binds DHCR7 and promotes its ubiquitination [PMID:41813657]. Loss of DHCR7 function produces 7-DHC accumulation and cholesterol deficiency with cell-type-specific consequences: it impairs serotonin1A receptor ligand binding through the altered sterol structure [PMID:17493586, PMID:17904101], disrupts primary ciliogenesis and downstream WNT/β-catenin and hedgehog signaling in osteoblasts to derail craniofacial bone formation [PMID:31934493], and acts upstream of SHH and BMP2 in palatal fusion [PMID:27066502]. Reduced enzymatic activity below a quantitative threshold causes Smith-Lemli-Opitz syndrome, with disease-associated missense mutations clustering in three protein domains and destabilizing the protein [PMID:15464432, PMID:11241839]. Tissue-selective transgenic rescue establishes that brain-autonomous DHCR7 activity is essential for neonatal survival, reflecting the blood-brain barrier's demarcation of fetal brain cholesterol synthesis [PMID:17408495, PMID:16651660]. DHCR7 also intersects innate immunity and cancer: Zika virus NS4B induces DHCR7 to suppress TBK1/IRF3 signaling and IFN-β production for immune evasion [PMID:36182074], 7-DHC accumulation activates AKT3–IRF3 neuroinflammatory signaling [PMID:38901498], and in cervical, thyroid, and myeloid malignancies DHCR7-driven cholesterol reprogramming activates PI3K/AKT, EGFR/ERK, and IL-6/JAK2/STAT3 pathways to promote tumor progression [PMID:38211648, PMID:41813657, PMID:41608869].","teleology":[{"year":2001,"claim":"Established that SLOS-associated DHCR7 missense mutations act through protein destabilization and map to defined domains, linking genotype to phenotype severity.","evidence":"Mutation expression studies and protein stability assays across patient cohorts with genotype-phenotype correlation","pmids":["11241839"],"confidence":"Medium","gaps":["No structural model of the active site","Mechanism by which destabilization translates to residual activity not quantified"]},{"year":2004,"claim":"Defined a quantitative enzymatic activity threshold below which DHCR7 deficiency causes SLOS, showing activity does not track clinical severity.","evidence":"Cell-based ergosterol-conversion activity assay across patient, carrier, and control primary cells","pmids":["15464432"],"confidence":"Medium","gaps":["Does not explain phenotypic variability independent of enzyme activity","Single lab"]},{"year":2006,"claim":"Resolved the developmental origin of brain versus peripheral cholesterol, showing the blood-brain barrier enforces autonomous fetal brain cholesterol synthesis.","evidence":"Isotopic tracing and GC-MS sterol profiling in Dhcr7-knockout fetuses across gestation","pmids":["16651660"],"confidence":"High","gaps":["Does not identify which CNS cell types require DHCR7","Mechanism of barrier restriction not addressed"]},{"year":2007,"claim":"Demonstrated tissue autonomy of DHCR7 function: peripheral rescue corrects lung and liver defects but CNS activity is uniquely required for survival.","evidence":"Liver-specific transgenic complementation in Dhcr7-null mice with tissue cholesterol biochemistry and survival analysis","pmids":["17408495"],"confidence":"High","gaps":["Does not define the brain cell type or developmental window of essentiality","Mechanism linking brain cholesterol to lethality unresolved"]},{"year":2007,"claim":"Showed that accumulated 7-DHC is functionally non-equivalent to cholesterol for membrane receptor function, providing a mechanistic basis for substrate-toxicity in deficiency.","evidence":"Cholesterol depletion/replenishment with radioligand binding of serotonin1A receptor in hippocampal membranes; replicated across two preparations","pmids":["17493586","17904101"],"confidence":"Medium","gaps":["Tested for one receptor only","Does not establish in vivo relevance"]},{"year":2009,"claim":"Revealed that DHCR7 overexpression severely disrupts ER and nuclear envelope organization, indicating dosage-sensitive membrane effects.","evidence":"Live-cell imaging and electron microscopy of overexpressed DHCR7 in multiple human cell lines","pmids":["19940018"],"confidence":"Medium","gaps":["Overexpression artifact versus physiological role unclear","Mechanism of membrane expansion not defined"]},{"year":2014,"claim":"Mapped transcriptional control of DHCR7 to cooperative SREBP-2 elements, embedding it in the sterol feedback response.","evidence":"Promoter-reporter assays, EMSA, and site-directed mutagenesis of SRE and NF-Y sites","pmids":["25048193"],"confidence":"Medium","gaps":["Tissue-specific transcriptional regulation not addressed","Single lab"]},{"year":2015,"claim":"Identified DHCR24 as a physical and functional partner controlling DHCR7 activity, supporting a terminal cholesterol metabolon with substrate channeling.","evidence":"Reciprocal Co-IP, siRNA knockdown, and overexpression activity assays","pmids":["25637936"],"confidence":"High","gaps":["Substrate channeling not directly demonstrated","Stoichiometry and structure of complex unknown"]},{"year":2016,"claim":"Established post-translational regulation of DHCR7 activity by phosphorylation at S14 via AMPK and PKA.","evidence":"Pharmacological kinase inhibition and S14 site-directed mutagenesis with cellular activity assay","pmids":["27520299"],"confidence":"Medium","gaps":["Direct kinase-substrate phosphorylation not shown","No independent replication"]},{"year":2016,"claim":"Placed DHCR7 upstream of SHH and BMP2 signaling in palatogenesis, with cholesterol supplementation rescuing the pathway defects.","evidence":"RNAi knockdown in palatal shelf explants with SEM, expression analysis, and cholesterol rescue","pmids":["27066502"],"confidence":"Medium","gaps":["Ex vivo culture only","Molecular link between cholesterol and Shh/Bmp2 expression unresolved"]},{"year":2020,"claim":"Linked DHCR7-dependent cholesterol status to primary ciliogenesis and WNT/hedgehog signaling in osteoblasts, explaining craniofacial bone defects.","evidence":"Conditional Dhcr7-knockout mouse, cilia and ciliary vesicle fusion assays, pathway reporters, and simvastatin rescue","pmids":["31934493"],"confidence":"High","gaps":["Mechanism connecting cholesterol to ciliary vesicle fusion not detailed","Generalizability beyond osteoblasts untested"]},{"year":2021,"claim":"Defined the substrate and inhibitor profile of the DHCR7 active site, distinguishing true substrates from inhibitors and excluding vitamin D3 derivatives.","evidence":"In vitro microsomal enzyme assays with multiple substrates and LC-MS product detection","pmids":["34098080"],"confidence":"High","gaps":["No atomic structure of active site","Performed with rat enzyme/microsomes"]},{"year":2022,"claim":"Uncovered a DHCR7 role in innate immune evasion, hijacked by Zika virus NS4B to suppress TBK1/IRF3 and interferon responses.","evidence":"Co-IP of NS4B-DHCR7, overexpression/knockdown, TBK1/IRF3 phosphorylation and IFN-β/ISG reporter assays","pmids":["36182074"],"confidence":"Medium","gaps":["Whether immune suppression requires catalytic activity or sterol products unclear","Single lab"]},{"year":2024,"claim":"Connected DHCR7 cholesterol reprogramming to cancer progression via KANK4/PI3K/AKT signaling and VEGF-C-driven lymphangiogenesis.","evidence":"Gain/loss-of-function in vitro, xenograft models, VEGF-C ELISA, and pathway Western blotting in cervical cancer","pmids":["38211648"],"confidence":"Medium","gaps":["Direct DHCR7-KANK4 mechanism not fully resolved","Single lab"]},{"year":2024,"claim":"Showed that autophagic degradation of DHCR7 drives 7-DHC accumulation and AKT3-IRF3 neuroinflammation in anesthesia-induced hippocampal injury.","evidence":"Autophagy inhibition (3-MA) in neonatal mouse and in vitro with DHCR7, 7-DHC, AKT3/IRF3 phosphorylation, and cytokine readouts","pmids":["38901498"],"confidence":"Medium","gaps":["Direct mechanism of 7-DHC activating AKT3 not defined","Single lab"]},{"year":2024,"claim":"Demonstrated that DHCR7 loss disrupts axonal autophagy and lysosome balance, linking sterol dysfunction to neuronal and behavioral phenotypes.","evidence":"dhcr7-knockout zebrafish with autophagy/lysosome markers, myelination/synapse imaging, and behavioral assays","pmids":["38626530"],"confidence":"Medium","gaps":["Causal link between autophagy defect and behavior not established","Single model organism study"]},{"year":2026,"claim":"Identified RTN3 as a regulator of DHCR7 stability through ubiquitination, controlling cholesterol-dependent EGFR/ERK activation in thyroid cancer.","evidence":"Co-IP, ubiquitination assay, knockdown/overexpression with pathway Western blotting, and simvastatin rescue","pmids":["41813657"],"confidence":"Medium","gaps":["E3 ligase mediating ubiquitination not identified","Single lab"]},{"year":2026,"claim":"Showed DHCR7 sustains AML through cholesterol homeostasis and IL-6/JAK2/STAT3 signaling, with inhibition triggering ER stress and apoptosis.","evidence":"siRNA knockdown and tamoxifen in AML lines, cholesterol/7-DHC and ER stress markers, JAK2/STAT3 assays, NSG xenografts","pmids":["41608869"],"confidence":"Medium","gaps":["Mechanism linking sterol changes to JAK2/STAT3 activation unresolved","Single lab"]},{"year":null,"claim":"How DHCR7's distinct downstream consequences—membrane receptor function, ciliary/hedgehog signaling, innate immunity, and oncogenic pathways—are mechanistically distinguished by 7-DHC toxicity versus cholesterol insufficiency remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No atomic structure of DHCR7 or the DHCR24 complex","Whether immune/oncogenic roles depend on catalysis or specific sterol species is unclear","The direct molecular sensors of 7-DHC accumulation are unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,5,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11,14,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,12]}],"complexes":[],"partners":["DHCR24","RTN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBM7","full_name":"7-dehydrocholesterol reductase","aliases":["Cholesterol-5,6-epoxide hydrolase subunit DHCR7","Delta7-sterol reductase","Sterol Delta(7)-reductase","Sterol reductase SR-2"],"length_aa":475,"mass_kda":54.5,"function":"Oxidoreductase that catalyzes the last step of the cholesterol synthesis pathway, which transforms cholesta-5,7-dien-3beta-ol (7-dehydrocholesterol,7-DHC) into cholesterol by reducing the C7-C8 double bond of its sterol core (PubMed:25637936, PubMed:38297129, PubMed:38297130, PubMed:9465114, PubMed:9634533). Can also metabolize cholesta-5,7,24-trien-3beta-ol (7-dehydrodemosterol, 7-DHD) to desmosterol, which is then metabolized by the Delta(24)-sterol reductase (DHCR24) to cholesterol (By similarity). Modulates ferroptosis (a form of regulated cell death driven by iron-dependent lipid peroxidation) through the metabolic breakdown of the anti-ferroptotic metabolites 7-DHC and 7-DHD which, when accumulated, divert the propagation of peroxyl radical-mediated damage from phospholipid components to its sterol core, protecting plasma and mitochondrial membranes from phospholipid autoxidation (PubMed:38297129, PubMed:38297130) Component of the microsomal antiestrogen binding site (AEBS), a multiproteic complex at the ER membrane that consists of an association between cholestenol Delta-isomerase/EBP and DHCR7 (PubMed:15175332, PubMed:20615952). This complex is responsible for cholesterol-5,6-epoxide hydrolase (ChEH) activity, which consists in the hydration of cholesterol-5,6-epoxides (5,6-EC) into cholestane-3beta,5alpha,6beta-triol (CT) (PubMed:20615952). The precise role of each component of this complex has not been described yet (PubMed:20615952)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9UBM7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DHCR7","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DHCR7","total_profiled":1310},"omim":[{"mim_id":"615465","title":"HARTSFIELD SYNDROME; HRTFDS","url":"https://www.omim.org/entry/615465"},{"mim_id":"615189","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 55; ANKRD55","url":"https://www.omim.org/entry/615189"},{"mim_id":"614969","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 7; 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This suggests a cholesterol 'metabolon' with substrate channeling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression activity assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional siRNA and overexpression rescue experiments in a single focused study; multiple orthogonal methods\",\n      \"pmids\": [\"25637936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Phosphorylation regulates DHCR7 enzymatic activity: pharmacological inhibition of AMP-activated protein kinase or protein kinase A significantly decreases DHCR7 activity, and mutation of a known phosphorylated residue (S14) also decreases activity, indicating phosphorylation is required for full catalytic function.\",\n      \"method\": \"Pharmacological kinase inhibitors, site-directed mutagenesis (S14 mutant), enzymatic activity assay in cells\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — mutagenesis plus pharmacological inhibition in a single lab study; no independent replication\",\n      \"pmids\": [\"27520299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The human DHCR7 promoter is transcriptionally regulated by SREBP-2 via two binding sites (at −155 and −55) and an NF-Y cofactor site (at −136). The two SREs cooperate synergistically to activate DHCR7 transcription in response to sterol depletion.\",\n      \"method\": \"Promoter-reporter assays, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis of SRE elements\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with mutagenesis and EMSA, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25048193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Wild-type DHCR7 (and the related sterol reductase TM7SF2) expression in human cell lines causes massive expansion of the endoplasmic reticulum and perinuclear space, including separation of inner and outer nuclear membranes, loss of nuclear pore complexes, and formation of cytoplasmic vacuoles — demonstrating that DHCR7 overexpression can severely disrupt ER and nuclear envelope organization.\",\n      \"method\": \"Live cell imaging, electron microscopy, overexpression of wild-type DHCR7 in multiple human cell lines\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging with EM validation in multiple cell lines, single lab\",\n      \"pmids\": [\"19940018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rat DHCR7 can reduce 20S(OH)7DHC and 27(OH)7DHC as substrates (removing the C7–C8 double bond), but lumisterol (L3), 8-DHC, and 7-dehydropregnenolone are not substrates — 8-DHC and 20S(OH)L3 act as inhibitors. Vitamin D3 and its hydroxy-derivatives do not inhibit DHCR7. This defines the substrate specificity and inhibitor profile of the active site.\",\n      \"method\": \"In vitro enzyme assay with rat liver microsomes, ergosterol-to-brassicasterol conversion inhibition screen, direct substrate testing by LC-MS product detection\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple substrates and mutagenesis-independent active-site screening; rigorous product identification by mass spectrometry\",\n      \"pmids\": [\"34098080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DHCR7 enzymatic activity (measured by ergosterol-to-brassicasterol conversion) is significantly reduced in fibroblasts, amniocytes, and chorionic villi from SLOS patients compared to carriers and controls, establishing a quantitative functional threshold (below ~8% conversion causes disease). Enzyme activity does not correlate with clinical severity score or plasma sterol ratios.\",\n      \"method\": \"Cell-based enzymatic activity assay (ergosterol conversion) in multiple primary cell types from patients, carriers, and controls\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — activity measured across multiple cell types with well-defined patient genotypes; single lab\",\n      \"pmids\": [\"15464432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Replenishment of 7-dehydrocholesterol (7-DHC) into cholesterol-depleted native hippocampal membranes does not restore ligand binding activity of the serotonin1A receptor, despite recovering overall membrane order — demonstrating that the structural difference introduced by DHCR7 substrate accumulation (the C7–C8 double bond) is functionally distinct from cholesterol for receptor function.\",\n      \"method\": \"Cholesterol depletion/replenishment in hippocampal membranes, radioligand binding assay, membrane order measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently in two separate papers (PMID 17493586 and 17904101) using both native and solubilized membrane preparations\",\n      \"pmids\": [\"17493586\", \"17904101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Zika virus non-structural protein NS4B physically interacts with DHCR7 and induces its expression. Upregulated DHCR7 in turn inhibits TBK1 and IRF3 phosphorylation, reducing IFN-β and interferon-stimulated gene production and thereby facilitating viral immune evasion. Blocking DHCR7 suppresses ZIKV infection.\",\n      \"method\": \"Co-immunoprecipitation (NS4B–DHCR7 interaction), overexpression/knockdown with DHCR7, phosphorylation assays for TBK1/IRF3, IFN-β and ISG reporter assays\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional signaling assays plus knockdown rescue, single lab\",\n      \"pmids\": [\"36182074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Disruption of Dhcr7 in osteoblasts alters intracellular cholesterol status, causing abnormalities in primary cilia number and length through dysregulated ciliary vesicle fusion, which in turn impairs WNT/β-catenin and hedgehog signaling and leads to defective osteoblast differentiation and craniofacial bone formation. Simvastatin treatment rescues ciliogenesis and osteogenesis defects.\",\n      \"method\": \"Conditional Dhcr7 knockout mouse model, primary cilia imaging, ciliary vesicle fusion assay, WNT/hedgehog pathway reporters, simvastatin rescue experiment\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific cellular phenotypes, pathway analysis by signaling reporters, and pharmacological rescue; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31934493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Liver-specific transgenic restoration of DHCR7 expression in Dhcr7-null mice normalizes cholesterol levels in liver and lung (80–90% of normal) and rescues late gestational lung sacculation defects, but does not rescue brain cholesterol deficiency or neonatal lethality, demonstrating that CNS-specific DHCR7 function is essential for survival.\",\n      \"method\": \"Liver-specific transgenic complementation (ApoE promoter-driven DHCR7), tissue cholesterol biochemistry, survival analysis in Dhcr7-null mice\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via tissue-selective transgenic rescue with biochemical validation; rigorous tissue-specific design establishing tissue autonomy\",\n      \"pmids\": [\"17408495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Dhcr7-knockout fetuses (which cannot convert 7-DHC to cholesterol), brain cholesterol is almost entirely of fetal/local origin from ~E11–12 onward (90% at birth), whereas peripheral organ cholesterol is substantially maternal in origin early in gestation, transitioning to predominantly fetal synthesis by birth. This establishes that the blood-brain barrier demarcates autonomous fetal brain cholesterol synthesis.\",\n      \"method\": \"Isotopic tracing using Dhcr7 knockout fetuses in heterozygous mothers; sterol profiling by GC-MS across gestational ages in brain, liver, and lung\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — elegant genetic model with rigorous biochemical sterol quantification; definitive origin-tracing experiment\",\n      \"pmids\": [\"16651660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHCR7 promotes cervical cancer lymph node metastasis via two mechanisms: (1) upregulating KANK4 and subsequently activating PI3K/AKT signaling, and (2) promoting secretion of VEGF-C to drive lymphangiogenesis. Both mechanisms require intact cholesterol reprogramming by DHCR7. DHCR7 inhibitors AY9944 and tamoxifen significantly inhibited lymph node metastasis in vivo.\",\n      \"method\": \"Gain- and loss-of-function experiments in vitro, xenograft mouse models in vivo, VEGF-C ELISA, PI3K/AKT pathway Western blotting, KANK4 interaction studies\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods in a single lab study\",\n      \"pmids\": [\"38211648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sevoflurane-induced autophagic degradation of DHCR7 causes accumulation of its substrate 7-DHC, which activates AKT3 and downstream IRF3-driven cytokine transcription (IL-6, TNF-α), leading to hippocampal neuroinflammation. Autophagy inhibitor 3-MA reverses DHCR7 degradation, AKT3 phosphorylation, IRF3 activation, and 7-DHC accumulation.\",\n      \"method\": \"Autophagy inhibition (3-MA) in neonatal mouse model and in vitro, DHCR7 protein quantification, 7-DHC measurement, AKT3 and IRF3 phosphorylation assays, cytokine measurements\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological intervention with matched biochemical readouts in both in vivo and in vitro systems; single lab\",\n      \"pmids\": [\"38901498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Inhibition of DHCR7 (the enzyme converting 7-DHC to cholesterol) in palatal shelf explants by RNAi causes failure of palatal fusion, accompanied by reduced expression of Shh and Bmp2. Exogenous cholesterol supplementation restores Shh and Bmp2 expression without affecting Dhcr7 silencing, placing DHCR7 upstream of SHH and BMP2 in palatogenesis.\",\n      \"method\": \"RNAi knockdown in palatal shelf culture, scanning electron microscopy, RT-PCR/Western blot for Shh and Bmp2, cholesterol rescue experiment\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with cholesterol rescue establishing pathway position; single lab, ex vivo culture system\",\n      \"pmids\": [\"27066502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RTN3 (reticulon 3) binds to DHCR7 and promotes its ubiquitination; downregulation of RTN3 stabilizes DHCR7, elevates cholesterol levels, and activates the EGFR/ERK pathway to promote thyroid cancer progression. Simvastatin (HMG-CoA reductase inhibitor) rescues the effects of RTN3 downregulation.\",\n      \"method\": \"Co-immunoprecipitation (RTN3–DHCR7), ubiquitination assay, knockdown/overexpression with pathway Western blotting, simvastatin rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional rescue; single lab\",\n      \"pmids\": [\"41813657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In dhcr7-deficient zebrafish, loss of DHCR7 function causes increased lysosomes and attenuated autophagy in axons, linking disrupted autophagy-related neuronal homeostasis to compromised myelination, synaptic anomalies, and neurotransmitter imbalances, as well as microcephaly and ADHD-like behavior.\",\n      \"method\": \"Dhcr7 knockout zebrafish (dhcr7-/-), lysosome and autophagy marker quantification, behavioral assays, myelination and synapse imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific cellular and behavioral phenotypes; single lab study in zebrafish\",\n      \"pmids\": [\"38626530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Expression studies of DHCR7 missense mutations identified in SLOS patients demonstrated decreased protein stability for all analyzed missense mutations. Clustering of mutations in three protein domains (transmembrane domain, fourth cytoplasmic loop, C-terminus) was established, with null and 4L mutations causing severe phenotype and TM/CT mutations causing mild phenotype, defining structure–function relationships.\",\n      \"method\": \"Mutation expression studies in cell lines, protein stability assays, clinical genotype-phenotype correlation across patient cohorts\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression studies with protein stability readout across multiple mutations; replicated in multiple patient cohorts\",\n      \"pmids\": [\"11241839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DHCR7 knockdown or treatment with tamoxifen in AML cells reduces intracellular cholesterol, causes 7-DHC accumulation, induces endoplasmic reticulum stress, triggers apoptosis, and suppresses leukaemia progression in NSG mouse models. Mechanistically, DHCR7 activates the IL-6/JAK2/STAT3 signalling axis in AML.\",\n      \"method\": \"siRNA knockdown and tamoxifen treatment in AML cell lines, cholesterol and 7-DHC measurement, ER stress markers, JAK2/STAT3 phosphorylation assays, NSG mouse xenograft model\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo methods; IL6/JAK2/STAT3 pathway mechanistic investigation; single lab\",\n      \"pmids\": [\"41608869\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DHCR7 is an endoplasmic reticulum-resident sterol reductase that catalyzes the final step of cholesterol biosynthesis (conversion of 7-dehydrocholesterol to cholesterol) in the Kandutsch-Russell pathway; its activity is regulated by SREBP-2-driven transcription (via cooperative SREs at −155 and −55 in the promoter), by phosphorylation at residue S14 (via AMPK and PKA), and by a physical and functional interaction with the terminal Bloch-pathway enzyme DHCR24, forming a putative cholesterol metabolon; substrate specificity studies show it acts on 7-DHC and selected hydroxy-derivatives but not lumisterol or vitamin D3; loss of DHCR7 function causes 7-DHC accumulation that impairs serotonin1A receptor function, disrupts primary ciliogenesis and downstream WNT/hedgehog signaling in osteoblasts, triggers autophagic–AKT3–IRF3 neuroinflammatory signaling, and compromises axonal autophagy in neurons, while tissue-selective rescue experiments establish that brain-autonomous DHCR7 activity is essential for neonatal survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DHCR7 is an endoplasmic reticulum sterol reductase that catalyzes the final step of cholesterol biosynthesis, reducing the C7–C8 double bond to convert 7-dehydrocholesterol (7-DHC) to cholesterol [#4, #5]. Substrate-specificity studies define a constrained active site that reduces 7-DHC and selected hydroxy-7DHC derivatives such as 20S(OH)7DHC and 27(OH)7DHC, while lumisterol, 8-DHC, and 7-dehydropregnenolone are not substrates and several of these instead act as inhibitors [#4]. The enzyme operates as part of a terminal cholesterol-synthesis unit through physical and functional interaction with DHCR24, with DHCR24 required for full DHCR7 activity, consistent with a substrate-channeling metabolon [#0]. DHCR7 output is controlled at multiple levels: transcriptionally by SREBP-2 acting through two cooperative sterol response elements and an NF-Y site in the promoter upon sterol depletion [#2], post-translationally by phosphorylation at S14 downstream of AMPK and PKA [#1], and by protein stability, as RTN3 binds DHCR7 and promotes its ubiquitination [#14]. Loss of DHCR7 function produces 7-DHC accumulation and cholesterol deficiency with cell-type-specific consequences: it impairs serotonin1A receptor ligand binding through the altered sterol structure [#6], disrupts primary ciliogenesis and downstream WNT/β-catenin and hedgehog signaling in osteoblasts to derail craniofacial bone formation [#8], and acts upstream of SHH and BMP2 in palatal fusion [#13]. Reduced enzymatic activity below a quantitative threshold causes Smith-Lemli-Opitz syndrome, with disease-associated missense mutations clustering in three protein domains and destabilizing the protein [#5, #16]. Tissue-selective transgenic rescue establishes that brain-autonomous DHCR7 activity is essential for neonatal survival, reflecting the blood-brain barrier's demarcation of fetal brain cholesterol synthesis [#9, #10]. DHCR7 also intersects innate immunity and cancer: Zika virus NS4B induces DHCR7 to suppress TBK1/IRF3 signaling and IFN-β production for immune evasion [#7], 7-DHC accumulation activates AKT3–IRF3 neuroinflammatory signaling [#12], and in cervical, thyroid, and myeloid malignancies DHCR7-driven cholesterol reprogramming activates PI3K/AKT, EGFR/ERK, and IL-6/JAK2/STAT3 pathways to promote tumor progression [#11, #14, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that SLOS-associated DHCR7 missense mutations act through protein destabilization and map to defined domains, linking genotype to phenotype severity.\",\n      \"evidence\": \"Mutation expression studies and protein stability assays across patient cohorts with genotype-phenotype correlation\",\n      \"pmids\": [\"11241839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the active site\", \"Mechanism by which destabilization translates to residual activity not quantified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a quantitative enzymatic activity threshold below which DHCR7 deficiency causes SLOS, showing activity does not track clinical severity.\",\n      \"evidence\": \"Cell-based ergosterol-conversion activity assay across patient, carrier, and control primary cells\",\n      \"pmids\": [\"15464432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not explain phenotypic variability independent of enzyme activity\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the developmental origin of brain versus peripheral cholesterol, showing the blood-brain barrier enforces autonomous fetal brain cholesterol synthesis.\",\n      \"evidence\": \"Isotopic tracing and GC-MS sterol profiling in Dhcr7-knockout fetuses across gestation\",\n      \"pmids\": [\"16651660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify which CNS cell types require DHCR7\", \"Mechanism of barrier restriction not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated tissue autonomy of DHCR7 function: peripheral rescue corrects lung and liver defects but CNS activity is uniquely required for survival.\",\n      \"evidence\": \"Liver-specific transgenic complementation in Dhcr7-null mice with tissue cholesterol biochemistry and survival analysis\",\n      \"pmids\": [\"17408495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the brain cell type or developmental window of essentiality\", \"Mechanism linking brain cholesterol to lethality unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that accumulated 7-DHC is functionally non-equivalent to cholesterol for membrane receptor function, providing a mechanistic basis for substrate-toxicity in deficiency.\",\n      \"evidence\": \"Cholesterol depletion/replenishment with radioligand binding of serotonin1A receptor in hippocampal membranes; replicated across two preparations\",\n      \"pmids\": [\"17493586\", \"17904101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tested for one receptor only\", \"Does not establish in vivo relevance\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed that DHCR7 overexpression severely disrupts ER and nuclear envelope organization, indicating dosage-sensitive membrane effects.\",\n      \"evidence\": \"Live-cell imaging and electron microscopy of overexpressed DHCR7 in multiple human cell lines\",\n      \"pmids\": [\"19940018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression artifact versus physiological role unclear\", \"Mechanism of membrane expansion not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped transcriptional control of DHCR7 to cooperative SREBP-2 elements, embedding it in the sterol feedback response.\",\n      \"evidence\": \"Promoter-reporter assays, EMSA, and site-directed mutagenesis of SRE and NF-Y sites\",\n      \"pmids\": [\"25048193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific transcriptional regulation not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified DHCR24 as a physical and functional partner controlling DHCR7 activity, supporting a terminal cholesterol metabolon with substrate channeling.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, and overexpression activity assays\",\n      \"pmids\": [\"25637936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate channeling not directly demonstrated\", \"Stoichiometry and structure of complex unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established post-translational regulation of DHCR7 activity by phosphorylation at S14 via AMPK and PKA.\",\n      \"evidence\": \"Pharmacological kinase inhibition and S14 site-directed mutagenesis with cellular activity assay\",\n      \"pmids\": [\"27520299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase-substrate phosphorylation not shown\", \"No independent replication\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed DHCR7 upstream of SHH and BMP2 signaling in palatogenesis, with cholesterol supplementation rescuing the pathway defects.\",\n      \"evidence\": \"RNAi knockdown in palatal shelf explants with SEM, expression analysis, and cholesterol rescue\",\n      \"pmids\": [\"27066502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ex vivo culture only\", \"Molecular link between cholesterol and Shh/Bmp2 expression unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked DHCR7-dependent cholesterol status to primary ciliogenesis and WNT/hedgehog signaling in osteoblasts, explaining craniofacial bone defects.\",\n      \"evidence\": \"Conditional Dhcr7-knockout mouse, cilia and ciliary vesicle fusion assays, pathway reporters, and simvastatin rescue\",\n      \"pmids\": [\"31934493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting cholesterol to ciliary vesicle fusion not detailed\", \"Generalizability beyond osteoblasts untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the substrate and inhibitor profile of the DHCR7 active site, distinguishing true substrates from inhibitors and excluding vitamin D3 derivatives.\",\n      \"evidence\": \"In vitro microsomal enzyme assays with multiple substrates and LC-MS product detection\",\n      \"pmids\": [\"34098080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic structure of active site\", \"Performed with rat enzyme/microsomes\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a DHCR7 role in innate immune evasion, hijacked by Zika virus NS4B to suppress TBK1/IRF3 and interferon responses.\",\n      \"evidence\": \"Co-IP of NS4B-DHCR7, overexpression/knockdown, TBK1/IRF3 phosphorylation and IFN-β/ISG reporter assays\",\n      \"pmids\": [\"36182074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether immune suppression requires catalytic activity or sterol products unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected DHCR7 cholesterol reprogramming to cancer progression via KANK4/PI3K/AKT signaling and VEGF-C-driven lymphangiogenesis.\",\n      \"evidence\": \"Gain/loss-of-function in vitro, xenograft models, VEGF-C ELISA, and pathway Western blotting in cervical cancer\",\n      \"pmids\": [\"38211648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DHCR7-KANK4 mechanism not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that autophagic degradation of DHCR7 drives 7-DHC accumulation and AKT3-IRF3 neuroinflammation in anesthesia-induced hippocampal injury.\",\n      \"evidence\": \"Autophagy inhibition (3-MA) in neonatal mouse and in vitro with DHCR7, 7-DHC, AKT3/IRF3 phosphorylation, and cytokine readouts\",\n      \"pmids\": [\"38901498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of 7-DHC activating AKT3 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that DHCR7 loss disrupts axonal autophagy and lysosome balance, linking sterol dysfunction to neuronal and behavioral phenotypes.\",\n      \"evidence\": \"dhcr7-knockout zebrafish with autophagy/lysosome markers, myelination/synapse imaging, and behavioral assays\",\n      \"pmids\": [\"38626530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between autophagy defect and behavior not established\", \"Single model organism study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified RTN3 as a regulator of DHCR7 stability through ubiquitination, controlling cholesterol-dependent EGFR/ERK activation in thyroid cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, knockdown/overexpression with pathway Western blotting, and simvastatin rescue\",\n      \"pmids\": [\"41813657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating ubiquitination not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed DHCR7 sustains AML through cholesterol homeostasis and IL-6/JAK2/STAT3 signaling, with inhibition triggering ER stress and apoptosis.\",\n      \"evidence\": \"siRNA knockdown and tamoxifen in AML lines, cholesterol/7-DHC and ER stress markers, JAK2/STAT3 assays, NSG xenografts\",\n      \"pmids\": [\"41608869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking sterol changes to JAK2/STAT3 activation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DHCR7's distinct downstream consequences—membrane receptor function, ciliary/hedgehog signaling, innate immunity, and oncogenic pathways—are mechanistically distinguished by 7-DHC toxicity versus cholesterol insufficiency remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic structure of DHCR7 or the DHCR24 complex\", \"Whether immune/oncogenic roles depend on catalysis or specific sterol species is unclear\", \"The direct molecular sensors of 7-DHC accumulation are unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11, 14, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DHCR24\", \"RTN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}