{"gene":"SREBF2","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1995,"finding":"SREBP2 (SREBF2) encodes a transcription factor with an NH2-terminal basic helix-loop-helix-leucine zipper (bHLH-Zip) domain followed by a membrane attachment domain; proteolytic cleavage by a sterol-regulated protease releases the bHLH-Zip domain from the membrane, allowing nuclear entry and transcriptional activation of sterol-regulated genes (LDL receptor, HMG-CoA synthase). SREBF2 maps to chromosome 22q13.","method":"Gene cloning, somatic cell hybrid analysis, fluorescence in situ hybridization, structural characterization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural characterization of the gene and protein domain architecture with functional description of proteolytic activation mechanism, foundational paper replicated across the field","pmids":["7759101"],"is_preprint":false},{"year":1997,"finding":"The SREBF2 gene spans 72 kb, comprises 19 exons and 18 introns, and contains a perfect 10-bp sterol regulatory element (SRE-1) in its own promoter region, indicating autoregulatory control of SREBP2 transcription by sterol levels.","method":"Gene cloning, sequencing, promoter analysis, transcription start site mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing and structural characterization of SREBF2 gene with identification of functional promoter SRE-1 element","pmids":["9070916"],"is_preprint":false},{"year":2004,"finding":"ATF6(N) (the cleaved nuclear form of ATF6) physically binds SREBP2(N) through its leucine-zipper domain, and the ATF6-SREBP2 complex on SRE-bound promoters recruits HDAC1, thereby suppressing SREBP2 transcriptional activity and reducing lipogenesis in liver cells. Glucose deprivation activates ATF6 and suppresses SREBP2-regulated transcription via this mechanism; blocking ATF6 cleavage by BiP/GRP78 reverses this inhibition.","method":"GST pull-down, co-immunoprecipitation, deletion mutagenesis, chromatin immunoprecipitation, overexpression in liver cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down and co-IP identifying direct interaction, ChIP showing complex at SRE, deletion mutagenesis mapping interaction domain, single lab with multiple orthogonal methods","pmids":["14765107"],"is_preprint":false},{"year":2006,"finding":"Overexpression of either ABCG1 or ABCG4 in CNS cells increases the proteolytic processing of SREBP2 to its transcriptionally active form, inducing SREBP2 target genes and cholesterol synthesis; conversely, Abcg1 or Abcg4 knockout represses SREBP2 target gene expression in brain. Both ABCG1 and ABCG4 reside in RhoB-positive endocytic vesicle membranes and regulate intracellular sterol/cholesterol distribution upstream of SREBP2 activation.","method":"Abcg4 knockout mice, primary cell culture (astrocytes, microglia, neurons, macrophages), overexpression, cellular localization studies, gene expression analysis","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model plus overexpression with defined SREBP2 processing readout; single lab","pmids":["17916878"],"is_preprint":false},{"year":2006,"finding":"SREBP2 directly binds to a sterol regulatory element (SRE) in the ABCA7 promoter and activates ABCA7 transcription in response to low cellular cholesterol, opposite to the LXR-driven regulation of ABCA1. Chromatin immunoprecipitation and promoter analysis identified the 9-bp SRE at positions −212 bp (mouse) and −179 bp (human) upstream of the ABCA7 transcription start site.","method":"Promoter analysis, SREBP2 forced expression/knockdown with siRNA, ChIP-implied promoter binding (promoter characterization with identified SRE)","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — promoter SRE identified and functional SREBP2 regulation confirmed by forced expression/siRNA, single lab, no direct ChIP for SREBP2 binding explicitly stated","pmids":["16788211"],"is_preprint":false},{"year":2010,"finding":"miR-33a is encoded within intron 16 of the SREBF2 gene and is co-expressed with SREBP2 mRNA. miR-33 targets the 3′ UTR of ABCA1 and ABCG1, suppressing their translation and reducing LXR-dependent cholesterol efflux to ApoAI and serum; hepatic overexpression of miR-33 decreases ABCA1 protein and plasma HDL, while miR-33 silencing increases them.","method":"Co-expression analysis, 3′ UTR targeting assays, hepatic overexpression and silencing of miR-33 in vivo, cholesterol efflux assays, plasma HDL measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional in vivo and in vitro assays with gain- and loss-of-function, replicated across multiple labs (PMID 20566875 and 20732877)","pmids":["20566875","20732877"],"is_preprint":false},{"year":2010,"finding":"miR-33, encoded within SREBF2 intron, also inhibits translation of CPT1A, HADHB, and CROT (proteins involved in fatty acid β-oxidation), thereby reducing fatty acid degradation in addition to suppressing ABCA1-mediated cholesterol export.","method":"Luciferase reporter assays, miRNA overexpression, protein expression analysis, fatty acid oxidation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple target validation with functional readout, replicated in independent lab (PMID 20732877)","pmids":["20732877"],"is_preprint":false},{"year":2010,"finding":"SREBP2 directly regulates NPC1L1 promoter activity and mRNA expression in a dose-dependent manner; chromatin immunoprecipitation confirmed that SREBP2 binds the NPC1L1 promoter in vivo in HuH7 cells. HNF1α also independently activates NPC1L1 transcription through a distinct HNF1 binding site.","method":"Correlation analysis in human liver samples, promoter-reporter assay, ChIP assay, SREBP2 and HNF1α overexpression in HuH7 cells","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming in vivo SREBP2 binding at NPC1L1 promoter, plus dose-dependent promoter reporter and mRNA assays; single lab","pmids":["20460578"],"is_preprint":false},{"year":2011,"finding":"Akt kinase activation (via IGF-1 stimulation or rapalog-induced Akt heterodimerization) acutely activates SREBP2 within 1 hour; pharmacological or siRNA-mediated Akt inhibition blunts SREBP2 activation, establishing Akt as a direct upstream activator of SREBP2 processing/activation in cholesterol metabolism.","method":"IGF-1 stimulation, pharmacological Akt inhibitors, siRNA knockdown of Akt, rapalog heterodimerization system for specific Akt activation, SREBP2 activation assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological inhibition, siRNA, and inducible Akt activation system) converging on same result; single lab","pmids":["22005015"],"is_preprint":false},{"year":2013,"finding":"LPS-activated TLR4-MyD88-NF-κB signaling increases SCAP expression and promotes its abnormal translocation from the ER to the Golgi, thereby activating the SCAP-SREBP2 pathway and upregulating LDLR and HMG-CoAR expression, leading to macrophage cholesterol accumulation and foam cell formation. Knockdown of MyD88 or SCAP, or blockade of IKK, each independently blocked this cross-talk.","method":"siRNA knockdown (MyD88, SCAP), IKK inhibitor, immunofluorescence/confocal microscopy for SCAP translocation, Western blot, RT-PCR, cholesterol measurement in macrophages","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNA targets and pharmacological inhibition with SCAP translocation imaging; single lab","pmids":["23335792"],"is_preprint":false},{"year":2014,"finding":"Hepatic insulin receptor signaling is required for SREBP-2 induction in response to feeding and statins; liver insulin receptor knockout (LIRKO) mice show 40% decrease in Srebp-2 and 50–90% decrease in cholesterologenic genes, abolish the fasting-to-refeeding induction of SREBP-2, and lose the statin-induced SREBP-2 response. Ezetimibe (which alters intrahepatic cholesterol) restores SREBP-2 induction, suggesting insulin regulates SREBP-2 indirectly through cholesterol distribution.","method":"Liver-specific insulin receptor knockout mice, microarray, mRNA and protein expression analysis, pharmacological treatments (statins, ezetimibe)","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean liver-specific KO with defined molecular phenotype; single lab with multiple methods","pmids":["24516236"],"is_preprint":false},{"year":2014,"finding":"Intestine-specific overexpression of active SREBP2 (driven by villin promoter in ISR2 transgenic mice) is sufficient to increase serum cholesterol in VLDL and LDL fractions and increase cholesterol and triglycerides in jejunum and liver, establishing that intestinal SREBP2 activation alone can drive hypercholesterolemia.","method":"Transgenic mouse model (villin-promoter driven active SREBP2), microarray of jejunal RNA, serum lipid and tissue lipid measurements","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific transgenic model with defined lipid phenotype; single lab","pmids":["24465397"],"is_preprint":false},{"year":2015,"finding":"SREBP-2 deficiency in mice causes embryonic lethality with defects in limb development and expression of morphogenic genes; surviving hypomorphic mice show reduced hepatic cholesterol, lower SREBP target gene expression, and near abolishment of hepatic Srebf1c transcripts, demonstrating that SREBP-2 is required for embryonic development and regulates SREBP-1c expression in a tissue-specific manner.","method":"SREBP-2 knockout and hypomorphic mouse generation, embryo analysis, gene expression analysis (mRNA, protein) in liver and adipose tissue","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO and hypomorphic mouse models with multiple defined phenotypic readouts across tissues; single lab but comprehensive genetic approach","pmids":["26685326"],"is_preprint":false},{"year":2015,"finding":"FXR activation by agonists (GSK2324 or GW4064) induces Srebp-2 mRNA and precursor SREBP-2 protein via an FXR response element within intron 10 of Srebp-2, and co-induces miR-33 (suppressing ABCA1, NSF, CPT1); however, nuclear active SREBP-2 and its target genes are not induced because FXR simultaneously induces INSIG-2A, which blocks SCAP-mediated SREBP-2 processing. This uncouples miR-33 expression from mature SREBP-2 activity. FXR-dependent induction of both Srebp-2 and miR-33 requires SCAP (absent in Scap-/- mice).","method":"FXR agonist treatment, ChIP-seq (FXR response element identification), Scap-/- mice, mRNA and protein expression analysis, gene target analysis","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq identification of FXR binding site, genetic knockout validation (Scap-/- mice), multiple molecular readouts; single lab","pmids":["25593129"],"is_preprint":false},{"year":2017,"finding":"CRTC2 (a transcription coactivator) regulates SREBP-2 transcription by interfering with FOXO1 recognition of insulin response element 1 (but not IRE2) in the SREBP-2 promoter, thereby inducing SREBP-2 and its target HMGCR to drive hepatic cholesterol synthesis. CRTC2 overexpression elevates liver cholesterol; SREBP-2 knockdown abolishes the CRTC2 effect on HMGCR.","method":"Adenovirus-mediated CRTC2 overexpression and CRTC2 knockout mice, in vivo HMGCR-luciferase imaging, promoter CRE/SRE mutation reporters, SREBP-2 siRNA rescue experiment","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo luciferase reporter with promoter mutagenesis, SREBP-2 KD rescue, and mouse models; single lab","pmids":["28395113"],"is_preprint":false},{"year":2011,"finding":"lop13 mice carry a spontaneous C3112T missense mutation (R1038C) in exon 18 of Srebf2, within its regulatory domain, causing nuclear cataracts, persistent skin wounds, and reduced cholesterol in brain, liver, and lens. Lack of complementation in Srebf2(lop13/GT) compound heterozygotes genetically confirms this hypomorphic Srebf2 mutation as causative, establishing Srebf2 as essential for lens and skin homeostasis.","method":"Linkage analysis, DNA sequencing, genetic complementation test (compound heterozygotes with gene-trap allele), gas chromatography for cholesterol measurement, histology","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic complementation test confirming causality, biochemical (GC) cholesterol measurements, multiple tissue phenotype analysis","pmids":["21858719"],"is_preprint":false},{"year":2020,"finding":"RNF5, an ER-anchored E3 ubiquitin ligase, mediates Lys-29-linked polyubiquitination of SCAP at Lys-305 (in cytosolic loop 2), which enhances the interaction between SCAP luminal loops 1 and 7 (a conformational change required for SREBP2 activation), thereby activating SREBP2 and promoting cholesterol biosynthesis. K305R SCAP variant fails to restore SREBP2 pathway in SCAP-deficient cells.","method":"RNF5 knockdown and overexpression in hepatoma cells, ubiquitination assays, mechanistic mutagenesis (K305R SCAP), interaction studies between SCAP luminal loops, rescue in SCAP-deficient cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination assays, site-specific mutagenesis, and complementation in deficient cell lines; single lab with multiple orthogonal methods","pmids":["32054686"],"is_preprint":false},{"year":2020,"finding":"SREBP2 directly induces transcription of Transferrin (TF) in melanoma circulating tumor cells, thereby reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, and conferring resistance to ferroptosis inducers. Knockdown of TF impairs tumor formation, partially rescued by lipophilic antioxidants.","method":"Single-cell RNA analysis of patient CTCs, SREBP2-driven TF transcription assay, TF knockdown, ferroptosis rescue experiments with ferrostatin-1 and vitamin E","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional regulation shown with knockdown functional phenotype; single lab with multiple orthogonal approaches","pmids":["33203734"],"is_preprint":false},{"year":2020,"finding":"Caspase-3 (CASP3) mediates cleavage of SREBP2 from the endoplasmic reticulum to promote cholesterol biosynthesis in hepatocellular carcinoma (HCC) cells, driving cancer stem cell expansion and resistance to sorafenib/lenvatinib treatment via activation of the sonic hedgehog signaling pathway. Loss of SREBP2 conferred sensitivity to tyrosine kinase inhibitors.","method":"RNA sequencing of drug-resistant patient-derived xenografts, SREBP2 loss-of-function (siRNA/CRISPR), caspase-3 cleavage assay, sonic hedgehog pathway analysis, xenograft mouse models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic cleavage assay with downstream pathway validation and in vivo xenograft; single lab","pmids":["35767704"],"is_preprint":false},{"year":2021,"finding":"Qki-5 functions as a transcriptional co-activator of Srebp2 in oligodendrocytes to control transcription of cholesterol biosynthesis genes. Qki depletion in neural stem cells or OPCs results in impaired cholesterol biosynthesis and defective myelinogenesis (without blocking oligodendrocyte differentiation), and substantially reduces brain cholesterol concentration.","method":"Qki conditional knockout in neural stem cells or OPCs in mice, RNA-seq, cholesterol measurement, functional myelination assessment","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific cellular readouts, co-activator role defined by genetic evidence; single lab","pmids":["33942715"],"is_preprint":false},{"year":2021,"finding":"AAV2/5-mediated delivery of the transcriptionally active N-terminal fragment of human SREBP2 specifically to striatal astrocytes in R6/2 Huntington's disease mice activates cholesterol biosynthesis pathway genes, restores synaptic transmission, reverses Drd2 transcript decline, clears mutant huntingtin aggregates, and attenuates behavioral deficits, establishing that glial SREBP2 participates in HD brain pathogenesis.","method":"AAV2/5 gene therapy in R6/2 HD mice, electrophysiology (synaptic transmission), gene expression analysis, immunohistochemistry for huntingtin aggregates, behavioral tests","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with multiple defined readouts; single lab","pmids":["33974044"],"is_preprint":false},{"year":2022,"finding":"Unspliced XBP1 (XBP1-u) colocalizes with SREBP2 and inhibits its ubiquitination/proteasomal degradation, thereby stabilizing SREBP2 and activating HMGCR transcription to promote cholesterol biosynthesis and tumorigenesis in HCC cells.","method":"Co-localization studies, ubiquitination assays, XBP1-u overexpression/knockdown, HMGCR expression analysis, tumor growth assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-localization and ubiquitination assay showing stabilization mechanism; single lab, limited mechanistic depth in abstract","pmids":["35933495"],"is_preprint":false},{"year":2022,"finding":"SREBF2 directly binds the promoter region of STARD4 (a mitochondrial cholesterol trafficking protein) to promote its transcription, increasing mitochondrial cholesterol levels and inhibiting cytochrome c release, thereby conferring sorafenib resistance in HCC. SREBF2 knockdown decreases mitochondrial cholesterol and increases cytochrome c release; STARD4 overexpression reverses SREBF2 knockdown effects.","method":"ChIP showing SREBF2 binding to STARD4 promoter, SREBF2/STARD4 siRNA knockdown, mitochondrial cholesterol measurement, cytochrome c release assay, sorafenib-resistant xenograft models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP, functional rescue experiments, in vivo xenograft; single lab","pmids":["35642354"],"is_preprint":false},{"year":2022,"finding":"USP28, a deubiquitinating enzyme, binds mature SREBP2, deubiquitinates it, and stabilizes it, thereby increasing expression of mevalonate pathway enzymes and metabolic flux. USP28 silencing reduces SREBP2 protein levels and renders cancer cells sensitive to statin treatment (rescued by geranyl-geranyl pyrophosphate).","method":"USP28 siRNA/CRISPR deletion, deubiquitination assays, co-immunoprecipitation (USP28-SREBP2 interaction), metabolic flux analysis, tissue microarray analysis, SREBP2 CRISPR KO mouse tumor model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assay, co-IP, in vivo tumor model, geranyl-geranyl pyrophosphate rescue; single lab","pmids":["37202505"],"is_preprint":false},{"year":2022,"finding":"KIF11 interacts with SREBP2 protein and attenuates its ubiquitination-mediated degradation, thereby enhancing SREBP2 protein stability and accumulation and upregulating mevalonate pathway genes (HMGCR, FDFT1, SQLE, MSMO1) and free cholesterol to drive pancreatic cancer progression.","method":"Co-immunoprecipitation (KIF11-SREBP2), ubiquitination assay, SREBP2-dependent rescue experiments, xenograft mouse model","journal":"Cancer medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP and ubiquitination assay; single lab, limited mechanistic detail in abstract","pmids":["35619540"],"is_preprint":false},{"year":2022,"finding":"Caffeine increases hepatic ER Ca2+ levels, which blocks transcriptional activation (proteolytic processing) of SREBP2, thereby reducing PCSK9 expression and increasing LDLR expression and LDL-cholesterol clearance. ER Ca2+ is identified as a regulator of SREBP2 activation.","method":"Caffeine treatment in hepatic cells and human volunteers, ER Ca2+ measurement, SREBP2 processing assay, PCSK9 and LDLR expression analysis, analog development","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between ER Ca2+ and SREBP2 processing demonstrated in cells and confirmed in human volunteers; single lab","pmids":["35140212"],"is_preprint":false},{"year":2020,"finding":"Endothelial HMGB1 regulates SREBP2 by prolonging its protein half-life (reducing its degradation rate); HMGB1 depletion reduces SREBP2 levels and consequently SR-BI expression, attenuating LDL transcytosis. Conversely, increased LDL causes SR-BI-dependent nuclear translocation of HMGB1. This HMGB1-SREBP2-SR-BI axis controls endothelial LDL transcytosis and atherosclerosis in vivo.","method":"siRNA knockdown in coronary artery endothelial cells, TIRF microscopy for LDL transcytosis, HMGB1 overexpression, SREBP2 half-life measurement, endothelial-specific HMGB1 KO mice, atherosclerosis assessment","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endothelial-specific KO mice with atherosclerosis readout, half-life measurements, TIRF microscopy; single lab","pmids":["33054399"],"is_preprint":false},{"year":2021,"finding":"SREBP2 overexpression in endothelial cells directly binds the promoter regions of mesenchymal genes (snai1, α-smooth muscle actin, vimentin, neural cadherin) and transactivates them, driving endothelial-to-mesenchymal transition. EC-specific SREBP2 transgenic mice show exacerbated vascular remodeling and mesenchymal transition after bleomycin-induced pulmonary fibrosis.","method":"SREBP2 overexpression transcriptomics, ChIP for promoter binding of mesenchymal genes, EC-specific transgenic SREBP2 mice, bleomycin pulmonary fibrosis model, epigenetic analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct promoter binding plus in vivo transgenic mouse model; single lab","pmids":["34806652"],"is_preprint":false},{"year":2023,"finding":"PKCλ/ι (an atypical PKC) phosphorylates SCAP, promoting its degradation and thereby inhibiting SREBP2 processing and activation. PKCλ/ι deficiency in intestinal epithelial cells upregulates SREBP2 and cholesterol biosynthesis, driving mesenchymal/serrated colorectal cancer initiation.","method":"PKCλ/ι conditional knockout in intestinal epithelial cells, SCAP phosphorylation/degradation assay, SREBP2 processing assay, mouse serrated tumor model, human sample validation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with SCAP phosphorylation mechanistic link to SREBP2; single lab","pmids":["38092754"],"is_preprint":false},{"year":2020,"finding":"NBEAL1, a Golgi-associated BEACH domain protein, regulates SREBP2 processing by interacting with SCAP and PAQR3, modulating LDLR expression. Reduced NBEAL1 expression leads to downregulation of LDLR and is associated with increased coronary artery disease risk.","method":"NBEAL1 knockdown/overexpression, co-immunoprecipitation (NBEAL1-SCAP-PAQR3 interaction), SREBP2 processing assay, LDLR expression analysis, human genetic association (eQTL)","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP identifying protein interaction and SREBP2 processing modulation; single lab, limited mechanistic depth in abstract","pmids":["32161285"],"is_preprint":false},{"year":2019,"finding":"SREBP2 directly binds the SRBEF2 (own gene) promoter SRE-1 element and also directly regulates SQLE gene promoter (through two newly identified SP1 and SREBF2 binding sites). OSBPL2 deletion inhibits AMPK signaling, allowing SP1 and SREBF2 to enter the nucleus and upregulate SQLE, increasing intracellular cholesterol and cholesteryl ester accumulation.","method":"CRISPR/Cas9 OSBPL2 knockout, RNA-seq, dual-luciferase reporter assay for SQLE promoter with transcription factor binding site mapping, AMPK signaling analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase reporter assay with site identification and AMPK pathway functional analysis; single lab","pmids":["31356817"],"is_preprint":false},{"year":2019,"finding":"Estrogen (E2) stimulates SREBP2 transcription in hepatic cells (HepG2, HuH-7) via a functional estrogen response element (ERE) in the SREBP2 promoter, to which ERα specifically binds; this is blocked by ERα antagonist. E2-driven SREBP2 induction increases HMGCR and LDLR expression and lipid secretion.","method":"Luciferase reporter assay with ERE and mutated ERE constructs, ChIP analysis confirming ERα binding at SREBP2 promoter, ERα antagonist treatment, RT-PCR and immunofluorescence","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming in vivo ERα binding, luciferase reporter with mutagenesis, receptor antagonist; single lab","pmids":["31827541"],"is_preprint":false},{"year":2017,"finding":"In neurons challenged with oligomeric Aβ42, SREBP2 activation is reduced because Aβ42 impairs Akt phosphorylation, which is required for SREBP2 transport from the ER to the Golgi (but does not affect enzymatic cleavage per se). Constitutively active Akt overexpression prevents Aβ42-induced SREBP2 inhibition and the downstream block of cholesterol synthesis and protein prenylation.","method":"Multiple neuronal cell types, oAβ42 treatment, Akt phosphorylation assay, SREBP2 activation assay, constitutively active Akt overexpression rescue, TgCRND8 AD mouse brain analysis","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic rescue with constitutively active Akt, in vivo AD mouse validation, multiple cell types; single lab","pmids":["29122977"],"is_preprint":false},{"year":2012,"finding":"TGF-β induces SREBP-2 and HMGCR expression in chondrocytes via integrin αV (ITGAV) and PI3K/Akt signaling. Smad3 interacts with SREBP-2. A functional SNP (1784G>C) in SREBP-2 causes upregulation of IL-1β and MMP-13 in chondrocytes. Integrin inhibition with cyclo-RGDFV peptide downregulates SREBP-2, HMGCR, phospho-PI3K, and MMP-13 and upregulates aggrecan.","method":"TGF-β treatment of normal chondrocytes, ITGAV/PI3K/Akt pathway analysis, Smad3-SREBP-2 interaction (implied), cyclo-RGDFV peptide treatment, SREBP-2 plasmid transfection with functional readouts","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell-based experiments with pathway inhibitors; interaction between Smad3 and SREBP2 not explicitly confirmed by Co-IP in abstract; single lab","pmids":["22662110"],"is_preprint":false},{"year":2013,"finding":"APP α-cleavage product (APPsα ectodomain) acts as a positive regulator of SREBP2 signaling in astrocytic, hepatic, and fibroblast cells, increasing SRE-dependent gene expression (~30%), cholesterol biosynthesis, and LDL receptor levels. The β-cleaved ectodomain represses SRE-dependent gene expression (~30%), establishing opposing paracrine regulators of SREBP2. In cholesterol-loaded cells (where β-cleavage dominates), this creates a feedback loop reducing cholesterol synthesis.","method":"APP cleavage product treatment in multiple human cell lines (U251MG, HepG2, fibroblasts), SRE-reporter assay, cholesterol biosynthesis and LDLR measurement, β-cleavage inhibitor experiments, patient fibroblast analysis","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell types and genetic conditions with SRE reporter, mechanistic rescue experiments; single lab","pmids":["24249638"],"is_preprint":false},{"year":2021,"finding":"SREBP2 directly binds the promoter region of YAP and transactivates it; uric acid/monosodium urate-induced SREBP2 in endothelial cells drives YAP signaling and pro-inflammatory gene expression. SREBP2 siRNA knockdown partially abolishes UA/MSU-induced YAP activity and monocyte adhesion; endothelial SREBP2 transgenic mice show activated YAP signaling.","method":"SREBP2 siRNA, adenovirus-SREBP2 overexpression with RNA-seq, SREBP2 endothelial transgenic mice, pharmacological SREBP2 inhibitor (betulin), promoter binding assay (implied), hyperuricemia mouse model","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic and pharmacological models with RNA-seq, siRNA rescue; YAP as direct SREBP2 transcriptional target established by gain-of-function; single lab","pmids":["33977576"],"is_preprint":false},{"year":2024,"finding":"Melanoma-derived lactate activates SREBP2 in tumor-infiltrating conventional dendritic cells, driving their transformation into mature regulatory DCs (mregDCs) via the mevalonate biosynthetic pathway. DC-specific genetic silencing or pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63 was identified as a surface marker for mregDCs.","method":"DC-specific SREBP2 genetic silencing, pharmacological SREBP2 inhibition, transcriptional and metabolic studies, lactate treatment of DCs, T cell activation assays, in vivo melanoma models, human sentinel lymph node analysis","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DC-specific genetic KD with defined immune phenotype and in vivo tumor suppression; single lab with multiple orthogonal methods","pmids":["38728412"],"is_preprint":false},{"year":2024,"finding":"ALOX15B-mediated lipid peroxidation activates ERK1/2 in macrophages, which in turn increases SREBP2 nuclear abundance and activity, controlling cholesterol biosynthesis. ALOX15B silencing reduces ERK1/2 activation and nuclear SREBP2, suppressing sterol biosynthetic intermediates (desmosterol, lathosterol) and making macrophages refractory to NPC1 inhibition-induced SREBP2 activation.","method":"ALOX15B siRNA in primary human macrophages, global transcriptome analysis, immunofluorescence for nuclear SREBP2, ERK1/2 inhibition, sterol biosynthetic intermediate measurement by mass spectrometry","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary human macrophages with transcriptome plus targeted biochemical validation of ERK1/2-SREBP2 axis; single lab","pmids":["38581859"],"is_preprint":false},{"year":2021,"finding":"SNX10 (sorting nexin 10) interacts with SCAP, and SNX10 deletion promotes dissociation of ERLIN2 from SCAP, enhancing SREBP2 activation and increasing intracellular cholesterol biosynthesis in intestinal stem cells, promoting their stemness. SNX10 conditional knockout in intestinal epithelial cells or ISCs promotes mucosal repair.","method":"SNX10 conditional knockout mice, ERLIN2-SCAP interaction analysis, SREBP2 activation assay, intracellular cholesterol measurement, ISC stemness assays, SNX10 small-molecule inhibitor (DC-SX029)","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined SCAP-ERLIN2 dissociation mechanism and SREBP2 activation readout; single lab","pmids":["37647408"],"is_preprint":false},{"year":2025,"finding":"Nuclear SREBP2 (nSREBP2) forms phase-separated condensates in the nucleus through its amino-terminal intrinsically disordered region (IDR). These condensates co-localize with transcription coactivators, partly on superenhancers, to activate lipogenic gene transcription. A conserved phenylalanine-to-alanine substitution in the IDR abolishes condensate formation and reduces transcriptional activity; fusion with a phase-separation-driving FUS-IDR rescues activity. Knock-in of this mutation in male mice impairs feeding-induced nSREBP2 activity and lowers hepatic and circulating cholesterol.","method":"Phase separation assays (condensate formation), IDR mutagenesis (Phe→Ala), FUS-IDR fusion rescue, ChIP-seq on superenhancers, knock-in mouse model, cholesterol measurement in vivo","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phase separation plus mutagenesis rescue, FUS-IDR fusion control, and in vivo knock-in mouse with functional metabolic readout; single lab with multiple orthogonal methods","pmids":["40394324"],"is_preprint":false},{"year":2021,"finding":"LPS increases SREBF2 expression via the TLR4/JNK/c-Jun signaling pathway, and simultaneously suppresses UBE2I-mediated SREBF2 sumoylation to enhance its transcriptional activity, resulting in increased intracellular cholesterol and ER stress (Bax upregulation) in portal vein endothelial cells.","method":"LPS treatment of endothelial cells, TLR4/JNK/c-Jun pathway analysis, sumoylation assay (UBE2I knockdown), SREBF2 expression and transcriptional activity assays, ER stress markers","journal":"Cell biology and toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway and sumoylation assays in single cell model; limited mechanistic depth in abstract; single lab","pmids":["33677747"],"is_preprint":false},{"year":2023,"finding":"Parkin expression level positively correlates with neuronal lipoprotein lipase (LPL) protein level and activity through SREBP2 as mediator; SREBP2 genetic ablation abolishes Parkin's effect on LPL expression. The Parkin-SREBP2-LPL pathway regulates intracellular lipid droplet formation and is upregulated by PD-linked oxidative stress (rotenone).","method":"Human neuroblastoma cell line and Parkin knockout mouse model, LPL activity assay, SREBP2 genetic ablation, lipid droplet assay, rotenone oxidative stress treatment","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with SREBP2 ablation rescue defining pathway position; single lab","pmids":["36519761"],"is_preprint":false},{"year":2020,"finding":"SREBP2 directly regulates LDLR transcription by binding its promoter; SREBP2 also indirectly regulates LDLR by increasing transcription of lncRNA LDLR-AS in fish hepatocytes. LDLR-AS functions as an RNA scaffold recruiting hnRNPR to the 5′ UTR of LDLR mRNA, stabilizing LDLR mRNA post-transcriptionally.","method":"SREBP2 knockdown, ChIP/reporter assay for LDLR promoter binding, LDLR-AS knockdown, RNA immunoprecipitation for hnRNPR binding, mRNA stability assay, triglyceride accumulation measurement (fish model)","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — fish (non-mammalian) model; SREBP2 direct promoter binding implied but mechanistic details limited in abstract; single lab","pmids":["35811843"],"is_preprint":false},{"year":2021,"finding":"SREBP2 binds to the promoter region of NLRC4 and activates its transcription in keratinocytes; LCN2 signaling through SREBP2 drives NLRC4-mediated inflammation in psoriasis. Suppressing SREBP2 in mice attenuated NLRC4 signaling and psoriasis-like dermatitis.","method":"ChIP showing SREBP2 binding to NLRC4 promoter, SREBP2 knockdown in mice, LCN2/24p3R silencing in psoriasis mouse model, in vitro keratinocyte assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct SREBP2-NLRC4 promoter binding with in vivo mouse model; single lab","pmids":["35120997"],"is_preprint":false},{"year":2022,"finding":"ZIKV infection increases recruitment of SREBP2 transcription factors to lipid gene promoters; pharmacological inhibition or genetic silencing of SREBP2 suppresses ZIKV infection of human dendritic cells, establishing SREBP2-activated lipid gene transcription as a mechanism exploited for viral replication.","method":"Genomics profiling of ZIKV-infected vs uninfected primary human DCs, ChIP for SREBP2 at lipid gene promoters, pharmacological SREBP2 inhibition, SREBP2 siRNA knockdown, ZIKV infectivity assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing SREBP2 recruitment, genetic and pharmacological loss-of-function with viral infectivity readout; single lab","pmids":["36097162"],"is_preprint":false},{"year":2018,"finding":"SREBP-2 pathway activity is required for the cytotoxicity of C. difficile toxins A and B; SREBP-2 regulates membrane cholesterol content, which is necessary for toxin pore formation in endosomal membranes and translocation of the glucosyltransferase domain. Pharmacological SREBP-2 pathway inhibition (PF-429242, 25-hydroxycholesterol, simvastatin) or SREBP-2 pathway-deficient cells protected against toxin intoxication; this protection was bypassed when the toxin's enzyme domain was delivered independently of pore formation.","method":"SREBP-2 pathway inhibitors (pharmacological and genetic), toxin B pore formation assay, anthrax protective antigen-mediated enzyme delivery (mechanistic bypass), cell viability assays","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic bypass experiment with anthrax PA delivery confirming pore formation dependence, multiple pharmacological inhibitors and pathway-deficient cells; single lab","pmids":["30592645"],"is_preprint":false},{"year":2019,"finding":"Elaidate (industrial trans fatty acid) activates SREBP2 via the SCAP-SREBP2 axis in hepatocytes by lowering intracellular free cholesterol levels, inducing cholesterol biosynthesis. This effect is SCAP-dependent but independent of liver-X receptor and UBXD8. Exogenous cholesterol represses, and elaidate attenuates, this anti-cholesterogenic feedback.","method":"Transcriptomics of hepatoma cells treated with elaidate vs oleate/palmitate, SCAP-dependent knockdown experiments, intracellular free cholesterol measurement, SREBP2 activity assay, diet-fed mouse model","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SCAP-dependent mechanism with gene knockdown and cholesterol measurement, plus in vivo mouse diet model; single lab","pmids":["31327168"],"is_preprint":false},{"year":2008,"finding":"In MFP2 (multifunctional protein 2, peroxisomal β-oxidation) knockout mice, PPAR-α activation by endogenous ligands (from accumulated peroxisomal substrates) leads to upregulation of SREBP2 and HMGCR; in MFP2/PPAR-α double knockout mice, SREBP2 and HMGCR upregulations are markedly attenuated, demonstrating a PPAR-α-dependent pathway for SREBP2 induction.","method":"MFP2 KO and MFP2/PPARα double KO mice, real-time PCR, gene expression profiling, cholesterol biosynthesis rate measurement","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double KO epistasis establishing PPAR-α dependence of SREBP2 induction; single lab","pmids":["18773970"],"is_preprint":false},{"year":2016,"finding":"Irisin activates AMPK in hepatocytes, which inhibits SREBP2 transcription and nuclear translocation, reducing hepatic cholesterol synthesis. AMPKα1 siRNA or compound C (AMPK inhibitor) blocks irisin-induced changes in SREBP2 and cholesterol levels, establishing AMPK as a required mediator between irisin and SREBP2.","method":"Irisin infusion in DIO mice, primary hepatocyte treatment, AMPK activation/inhibition (compound C, AMPKα1 siRNA), SREBP2 nuclear translocation assay, cholesterol measurement","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA) and pharmacological AMPK inhibition with SREBP2 nuclear translocation assay in vivo and in vitro; single lab","pmids":["27211556"],"is_preprint":false},{"year":2020,"finding":"SREBP2 directly induces transcription of PCSK9 via the sterol regulatory element in its promoter; caffeine blocks this by increasing ER Ca2+. PXR activation increases proteolytic activation of SREBP2 (SCAP-mediated), driving widespread induction of cholesterol synthesis genes and PCSK9 in mice and humans.","method":"PXR ligand (rifampicin) treatment in humans and mice, NMR metabolomics, PXR KO mice, cholesterol synthesis intermediate measurement (lathosterol ratio), PCSK9 plasma measurement","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human crossover study plus PXR KO mice with cholesterol synthesis intermediates and PCSK9 as readouts; single lab with clinical confirmation","pmids":["33687065"],"is_preprint":false}],"current_model":"SREBP2 (encoded by SREBF2) is a membrane-bound bHLH-leucine zipper transcription factor that, under cholesterol-deficient conditions, undergoes SCAP-mediated ER-to-Golgi transport and proteolytic cleavage to release its N-terminal domain, which enters the nucleus to activate sterol-responsive target genes (LDLR, HMGCR, PCSK9, STARD4, NPC1L1, and others); nuclear SREBP2 activity is enhanced by phase-separated condensate formation via its N-terminal intrinsically disordered region; upstream regulators include Akt (required for ER-to-Golgi transport), AMPK (inhibitory), RNF5 (E3 ligase ubiquitinating SCAP to promote activation), USP28 (deubiquitinase stabilizing mature SREBP2), ATF6 (which binds SREBP2 via its leucine-zipper domain and recruits HDAC1 to suppress activity), FXR (which induces Srebp2 transcription but simultaneously induces INSIG-2A to block processing), and ER Ca2+ (required for processing); the SREBF2 locus is bifunctional, also encoding intronic miR-33a, which post-transcriptionally suppresses ABCA1, ABCG1, and fatty acid β-oxidation enzymes (CPT1A, HADHB, CROT) to complement SREBP2-driven lipid anabolism; SREBP2 plays essential roles in embryonic development, myelinogenesis (as a Qki co-activator in oligodendrocytes), neuronal cholesterol homeostasis, immune cell function (including tolerogenic DC differentiation driven by tumor lactate), and is co-opted in multiple cancers through mechanisms including caspase-3-mediated cleavage and deubiquitination by USP28."},"narrative":{"mechanistic_narrative":"SREBF2 encodes SREBP2, a membrane-bound basic helix-loop-helix-leucine zipper transcription factor that serves as a master regulator of cholesterol homeostasis: under sterol-poor conditions a sterol-regulated protease cleaves the membrane-attached precursor to release its N-terminal bHLH-Zip domain, which enters the nucleus to transactivate sterol-responsive genes [PMID:7759101]. SREBP2 is subject to negative feedback through a perfect sterol regulatory element (SRE-1) in its own promoter, providing autoregulatory control by sterol levels [PMID:9070916, PMID:31356817]. Its direct transcriptional target repertoire spans cholesterol uptake and synthesis (LDLR, HMGCR, PCSK9, NPC1L1, SQLE, the lipid transporters ABCA7 and STARD4) [PMID:16788211, PMID:20460578, PMID:35642354, PMID:31356817, PMID:33687065], and the locus is bifunctional, co-expressing intronic miR-33a that post-transcriptionally suppresses ABCA1, ABCG1, and fatty-acid β-oxidation enzymes (CPT1A, HADHB, CROT), coupling SREBP2-driven anabolism to repression of cholesterol efflux and lipid catabolism [PMID:20566875, PMID:20732877]. SREBP2 activation is gated at the proteolytic-processing step by the SCAP machinery, which integrates numerous inputs: Akt is required for ER-to-Golgi transport of SREBP2 [PMID:22005015, PMID:29122977], RNF5-mediated ubiquitination of SCAP promotes the conformational change needed for activation [PMID:32054686], AMPK signaling is inhibitory [PMID:27211556], ER Ca2+ is required for processing [PMID:35140212], and the mature nuclear protein is stabilized against ubiquitin-dependent degradation by USP28 [PMID:37202505]. Nuclear SREBP2 acts through phase-separated condensates formed by its N-terminal intrinsically disordered region, which co-localize with coactivators at superenhancers to drive lipogenic transcription; abolishing condensate formation lowers transcriptional activity and circulating cholesterol [PMID:40394324]. SREBP2 is essential for embryonic development and tissue homeostasis—its loss causes embryonic lethality and limb defects, and a hypomorphic point mutation produces nuclear cataracts and skin defects with reduced tissue cholesterol [PMID:26685326, PMID:21858719]—and it has dedicated roles in oligodendrocyte myelinogenesis as a Qki co-activated regulator of brain cholesterol synthesis [PMID:33942715]. Beyond canonical lipid metabolism, SREBP2 directly transactivates non-lipogenic targets to drive disease programs, including mesenchymal genes in endothelial-to-mesenchymal transition [PMID:34806652], NLRC4 in keratinocyte inflammation [PMID:35120997], and transferrin to suppress ferroptosis [PMID:33203734], and is co-opted across cancers and pathogens through caspase-3-mediated cleavage and stabilization [PMID:35767704, PMID:36097162, PMID:38728412].","teleology":[{"year":1995,"claim":"Established the founding mechanistic model: SREBP2 is a membrane-tethered bHLH-Zip transcription factor activated by sterol-regulated proteolysis that liberates a nuclear transcriptional domain.","evidence":"Gene cloning, FISH mapping, and structural characterization defining domain architecture and proteolytic activation","pmids":["7759101"],"confidence":"High","gaps":["Identity of the regulated protease and the full upstream transport machinery not resolved here","Genome-wide target spectrum unknown at this stage"]},{"year":1997,"claim":"Defined the autoregulatory logic of the pathway by locating a functional SRE-1 in the SREBF2 promoter, showing the transcription factor regulates its own gene by sterol levels.","evidence":"Genomic cloning, sequencing, and promoter analysis of the 19-exon SREBF2 locus","pmids":["9070916"],"confidence":"High","gaps":["Did not establish quantitative feedback dynamics in vivo"]},{"year":2004,"claim":"Identified a direct protein-protein brake on SREBP2 output: ATF6(N) binds SREBP2(N) via its leucine zipper and recruits HDAC1 at SRE promoters to suppress lipogenesis, linking the unfolded protein response to cholesterol synthesis.","evidence":"Reciprocal GST pull-down/co-IP, deletion mapping, and ChIP in liver cells under glucose deprivation","pmids":["14765107"],"confidence":"High","gaps":["Stoichiometry and genomic breadth of ATF6-SREBP2 co-occupancy not defined","In vivo physiological contribution not quantified"]},{"year":2006,"claim":"Expanded the direct target set to lipid transporters, showing SREBP2 binds SREs in ABCA7 (opposite to LXR) and that ABCG1/ABCG4-controlled sterol distribution feeds back on SREBP2 processing.","evidence":"Promoter/SRE analysis with forced expression and siRNA (ABCA7); Abcg4 knockout plus overexpression with SREBP2 processing readout (CNS cells)","pmids":["16788211","17916878"],"confidence":"Medium","gaps":["Direct ChIP for SREBP2 at ABCA7 not explicitly shown","Tissue specificity of these regulatory relationships incompletely mapped"]},{"year":2010,"claim":"Revealed the SREBF2 locus as bifunctional: intronic miR-33a is co-expressed with SREBP2 and suppresses ABCA1/ABCG1 and β-oxidation enzymes, coordinating anabolic transcription with repression of efflux and catabolism.","evidence":"3' UTR/luciferase target validation, hepatic gain/loss of function in vivo, cholesterol efflux and HDL measurement; replicated across labs","pmids":["20566875","20732877"],"confidence":"High","gaps":["Relative contribution of miR-33 vs SREBP2 protein to net lipid phenotype not partitioned"]},{"year":2010,"claim":"Extended direct transcriptional targeting to the intestinal sterol absorption transporter NPC1L1, confirmed by in vivo promoter occupancy.","evidence":"Promoter-reporter, ChIP in HuH7 cells, and dose-dependent overexpression","pmids":["20460578"],"confidence":"Medium","gaps":["Physiological impact on dietary cholesterol absorption not tested genetically"]},{"year":2011,"claim":"Placed Akt kinase as a direct upstream activator acting on the processing/transport step, linking growth-factor signaling to acute SREBP2 activation.","evidence":"IGF-1 stimulation, Akt inhibitors, siRNA, and rapalog-inducible Akt heterodimerization with SREBP2 activation assay","pmids":["22005015"],"confidence":"Medium","gaps":["Direct phosphorylation substrate within the transport machinery not pinpointed in this study"]},{"year":2014,"claim":"Established physiological in vivo control nodes: hepatic insulin receptor signaling is required for feeding- and statin-induced SREBP2 (likely via cholesterol distribution), and intestinal SREBP2 activation alone is sufficient to cause hypercholesterolemia.","evidence":"Liver-specific insulin receptor knockout with ezetimibe rescue; villin-promoter active-SREBP2 transgenic mice with lipid phenotyping","pmids":["24516236","24465397"],"confidence":"Medium","gaps":["Mechanistic link between insulin and intracellular cholesterol redistribution remains indirect"]},{"year":2015,"claim":"Demonstrated SREBP2 is essential for embryonic development and that its activity can be uncoupled from its transcription, since FXR induces Srebp2 mRNA and miR-33 yet blocks mature protein production by inducing INSIG-2A.","evidence":"SREBP2 knockout/hypomorphic mice with embryo analysis; FXR agonists, ChIP-seq FXR response element, and Scap-/- validation","pmids":["26685326","25593129"],"confidence":"High","gaps":["Developmental targets of SREBP2 driving limb/morphogenic defects not identified","Physiological settings where the transcription/processing uncoupling dominates not delineated"]},{"year":2015,"claim":"Genetically confirmed SREBP2 as essential for tissue homeostasis: a hypomorphic regulatory-domain missense mutation causes cataracts, skin defects, and reduced tissue cholesterol, with causality proven by complementation testing.","evidence":"lop13 spontaneous R1038C mutant, linkage, complementation with gene-trap allele, GC cholesterol measurement","pmids":["21858719"],"confidence":"High","gaps":["Molecular consequence of the R1038C regulatory-domain mutation on processing not mechanistically dissected"]},{"year":2020,"claim":"Resolved how SCAP conformational activation is post-translationally licensed and how mature SREBP2 abundance is controlled, identifying RNF5-mediated SCAP ubiquitination and USP28 deubiquitination of nuclear SREBP2 as opposing controls.","evidence":"RNF5 ubiquitination assays and K305R SCAP rescue; USP28 co-IP, deubiquitination assays, and statin-sensitivity rescue with GGPP","pmids":["32054686","37202505"],"confidence":"High","gaps":["Counteracting E3 ligase for mature SREBP2 not defined","Signals that toggle RNF5/USP28 activity not established"]},{"year":2020,"claim":"Uncovered non-canonical SREBP2 functions beyond lipid synthesis, including direct transactivation of transferrin to suppress ferroptosis in metastatic melanoma and caspase-3-mediated cleavage driving cancer stemness and drug resistance.","evidence":"Single-cell CTC analysis with TF knockdown and ferroptosis rescue; caspase-3 cleavage assay, SREBP2 loss-of-function, and xenografts in HCC","pmids":["33203734","35767704"],"confidence":"Medium","gaps":["Generality of caspase-3 cleavage as a physiological activation route unclear","Whether TF is a canonical SRE-driven target not detailed"]},{"year":2021,"claim":"Defined a tissue-specific developmental role through co-activator partnership, with Qki-5 acting as a transcriptional co-activator of Srebp2 to drive oligodendrocyte cholesterol synthesis and myelinogenesis.","evidence":"Qki conditional knockout in neural stem cells/OPCs with RNA-seq, cholesterol measurement, and myelination assays","pmids":["33942715"],"confidence":"Medium","gaps":["Direct biochemical Qki-SREBP2 interaction interface not mapped"]},{"year":2021,"claim":"Showed SREBP2 directly transactivates non-lipogenic disease-driver genes, binding promoters of mesenchymal genes (EndMT) and YAP and NLRC4 in inflammation.","evidence":"ChIP for promoter binding, EC-specific transgenic mice, and siRNA rescue across fibrosis, hyperuricemia, and psoriasis models","pmids":["34806652","33977576","35120997"],"confidence":"Medium","gaps":["Whether these targets require canonical SREs or alternative motifs not resolved","Sterol-dependence of these programs unclear"]},{"year":2022,"claim":"Identified ER Ca2+ as a required input to processing and mapped additional protein stabilizers (XBP1-u, KIF11) and a direct mitochondrial-cholesterol target (STARD4), explaining drug-resistance phenotypes in cancer.","evidence":"Caffeine/ER-Ca2+ manipulation with processing and PCSK9/LDLR readout; co-localization/ubiquitination assays; ChIP at STARD4 promoter with rescue","pmids":["35140212","35933495","35642354","35619540"],"confidence":"Medium","gaps":["KIF11-SREBP2 interaction rests on single co-IP without reciprocal validation","Mechanism by which ER Ca2+ gates SCAP-mediated processing not detailed"]},{"year":2023,"claim":"Continued mapping of upstream SCAP-level regulators, adding PKCλ/ι phosphorylation-driven SCAP degradation and SNX10-controlled ERLIN2-SCAP dissociation as brakes whose loss drives intestinal tumor/stem-cell programs.","evidence":"Conditional knockouts in intestinal epithelium with SCAP phosphorylation/degradation and SREBP2 processing assays","pmids":["38092754","37647408"],"confidence":"Medium","gaps":["Interplay among RNF5, PKCλ/ι, SNX10, and ERLIN2 at SCAP not integrated"]},{"year":2024,"claim":"Linked SREBP2 to tumor immune evasion and lipid-peroxidation signaling, showing tumor lactate activates SREBP2 to generate immunosuppressive regulatory dendritic cells and that ALOX15B-ERK1/2 raises nuclear SREBP2 in macrophages.","evidence":"DC-specific SREBP2 silencing with T-cell and tumor readouts; ALOX15B siRNA in primary human macrophages with sterol-intermediate mass spectrometry","pmids":["38728412","38581859"],"confidence":"Medium","gaps":["Whether SREBP2's immunosuppressive role is purely mevalonate-dependent not fully separated"]},{"year":2025,"claim":"Provided a biophysical mechanism for nuclear SREBP2 transactivation, showing its N-terminal IDR drives phase-separated condensates at superenhancers required for full lipogenic transcription in vivo.","evidence":"Phase-separation assays, IDR Phe→Ala mutagenesis with FUS-IDR rescue, ChIP-seq, and knock-in mouse with cholesterol phenotyping","pmids":["40394324"],"confidence":"High","gaps":["Coactivators recruited into condensates not exhaustively identified","How sterol signaling tunes condensate dynamics unknown"]},{"year":null,"claim":"How the many upstream SCAP-level regulators, nuclear stabilizers, and condensate dynamics are integrated into a unified quantitative model of context-specific SREBP2 output, and which mechanisms govern its expanding non-lipogenic target programs, remain open.","evidence":"No single study in the corpus integrates these layers mechanistically","pmids":[],"confidence":"Low","gaps":["No unified model linking processing-level and stability-level control","Sterol-dependence of non-canonical targets unresolved","Structural basis of target selection between lipogenic and non-lipogenic promoters unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,4,7,22,27,30,43,49]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,7,22,27,30]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,18,25,32]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,39,48]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[9,29]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5,6,30,46,49]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,4,7,22,27,30,43]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,25,32]}],"complexes":[],"partners":["SCAP","ATF6","USP28","RNF5","QKI","XBP1","KIF11","AKT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12772","full_name":"Sterol regulatory element-binding protein 2","aliases":["Class D basic helix-loop-helix protein 2","bHLHd2","Sterol regulatory element-binding transcription factor 2"],"length_aa":1141,"mass_kda":123.7,"function":"Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 2), which is embedded in the endoplasmic reticulum membrane (PubMed:32322062). Low sterol concentrations promote processing of this form, releasing the transcription factor form that translocates into the nucleus and activates transcription of genes involved in cholesterol biosynthesis (PubMed:32322062) Key transcription factor that regulates expression of genes involved in cholesterol biosynthesis (PubMed:12177166, PubMed:32322062). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:12177166, PubMed:7903453). Regulates transcription of genes related to cholesterol synthesis pathway (PubMed:12177166, PubMed:32322062)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q12772/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SREBF2","classification":"Not Classified","n_dependent_lines":72,"n_total_lines":1208,"dependency_fraction":0.059602649006622516},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SREBF2","total_profiled":1310},"omim":[{"mim_id":"621173","title":"G PROTEIN-COUPLED RECEPTOR 146; GPR146","url":"https://www.omim.org/entry/621173"},{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"},{"mim_id":"613486","title":"MICRO RNA 33B; MIR33B","url":"https://www.omim.org/entry/613486"},{"mim_id":"612912","title":"TRANSMEMBRANE PROTEIN 97; TMEM97","url":"https://www.omim.org/entry/612912"},{"mim_id":"612156","title":"MICRO RNA 33A; MIR33A","url":"https://www.omim.org/entry/612156"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SREBF2"},"hgnc":{"alias_symbol":["SREBP2","bHLHd2"],"prev_symbol":[]},"alphafold":{"accession":"Q12772","domains":[{"cath_id":"4.10.280.10","chopping":"338-399","consensus_level":"medium","plddt":86.3252,"start":338,"end":399},{"cath_id":"-","chopping":"756-818_831-852_863-912","consensus_level":"medium","plddt":75.9667,"start":756,"end":912},{"cath_id":"1.20.1310","chopping":"943-1045","consensus_level":"medium","plddt":83.3946,"start":943,"end":1045},{"cath_id":"1.25.40","chopping":"1054-1059_1074-1141","consensus_level":"medium","plddt":76.8405,"start":1054,"end":1141}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12772","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12772-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12772-F1-predicted_aligned_error_v6.png","plddt_mean":61.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SREBF2","jax_strain_url":"https://www.jax.org/strain/search?query=SREBF2"},"sequence":{"accession":"Q12772","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12772.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12772/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12772"}},"corpus_meta":[{"pmid":"20566875","id":"PMC_20566875","title":"miR-33 links SREBP-2 induction to repression of sterol transporters.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20566875","citation_count":468,"is_preprint":false},{"pmid":"20732877","id":"PMC_20732877","title":"Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20732877","citation_count":304,"is_preprint":false},{"pmid":"19231010","id":"PMC_19231010","title":"Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.","date":"2009","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/19231010","citation_count":293,"is_preprint":false},{"pmid":"7759101","id":"PMC_7759101","title":"Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to 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a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31417158","citation_count":15,"is_preprint":false},{"pmid":"35244192","id":"PMC_35244192","title":"LncCCAT1 interaction protein PKM2 upregulates SREBP2 phosphorylation to promote osteosarcoma tumorigenesis by enhancing the Warburg effect and lipogenesis.","date":"2022","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35244192","citation_count":15,"is_preprint":false},{"pmid":"32751718","id":"PMC_32751718","title":"Regulatory Roles of SREBF1 and SREBF2 in Lipid Metabolism and Deposition in Two Chinese Representative Fat-Tailed Sheep Breeds.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32751718","citation_count":14,"is_preprint":false},{"pmid":"35172278","id":"PMC_35172278","title":"The elevation of miR-185-5p alleviates high-fat diet-induced atherosclerosis and lipid accumulation in vivo and in vitro via SREBP2 activation.","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/35172278","citation_count":14,"is_preprint":false},{"pmid":"32195924","id":"PMC_32195924","title":"Expression of SREBP2 and cholesterol metabolism related genes in TCGA glioma cohorts.","date":"2020","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32195924","citation_count":13,"is_preprint":false},{"pmid":"38442806","id":"PMC_38442806","title":"Hawthorn leaf flavonoids alleviate the deterioration of atherosclerosis by inhibiting SCAP-SREBP2-LDLR pathway through sPLA2-ⅡA signaling in macrophages in mice.","date":"2024","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38442806","citation_count":13,"is_preprint":false},{"pmid":"36610166","id":"PMC_36610166","title":"Tilianin improves lipid profile and alleviates atherosclerosis in ApoE-/- mice through up-regulation of SREBP2-mediated LDLR expression.","date":"2022","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36610166","citation_count":13,"is_preprint":false},{"pmid":"36519761","id":"PMC_36519761","title":"Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway-implications for Parkinson's disease.","date":"2023","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36519761","citation_count":12,"is_preprint":false},{"pmid":"21858719","id":"PMC_21858719","title":"A spontaneous mutation in Srebf2 leads to cataracts and persistent skin wounds in the lens opacity 13 (lop13) mouse.","date":"2011","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/21858719","citation_count":12,"is_preprint":false},{"pmid":"38030791","id":"PMC_38030791","title":"The RORɣ/SREBP2 pathway is a master regulator of cholesterol metabolism and serves as potential therapeutic target in t(4;11) leukemia.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38030791","citation_count":12,"is_preprint":false},{"pmid":"39775479","id":"PMC_39775479","title":"Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39775479","citation_count":12,"is_preprint":false},{"pmid":"40394324","id":"PMC_40394324","title":"Nuclear SREBP2 condensates regulate the transcriptional activation of lipogenic genes and cholesterol homeostasis.","date":"2025","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40394324","citation_count":11,"is_preprint":false},{"pmid":"33677747","id":"PMC_33677747","title":"SREBF2 triggers endoplasmic reticulum stress and Bax dysregulation to promote lipopolysaccharide-induced endothelial cell injury.","date":"2021","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33677747","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53630,"output_tokens":13968,"usd":0.185205,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":26338,"output_tokens":6155,"usd":0.142783,"stage2_stop_reason":"end_turn"},"total_usd":0.327988,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"SREBP2 (SREBF2) encodes a transcription factor with an NH2-terminal basic helix-loop-helix-leucine zipper (bHLH-Zip) domain followed by a membrane attachment domain; proteolytic cleavage by a sterol-regulated protease releases the bHLH-Zip domain from the membrane, allowing nuclear entry and transcriptional activation of sterol-regulated genes (LDL receptor, HMG-CoA synthase). SREBF2 maps to chromosome 22q13.\",\n      \"method\": \"Gene cloning, somatic cell hybrid analysis, fluorescence in situ hybridization, structural characterization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural characterization of the gene and protein domain architecture with functional description of proteolytic activation mechanism, foundational paper replicated across the field\",\n      \"pmids\": [\"7759101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The SREBF2 gene spans 72 kb, comprises 19 exons and 18 introns, and contains a perfect 10-bp sterol regulatory element (SRE-1) in its own promoter region, indicating autoregulatory control of SREBP2 transcription by sterol levels.\",\n      \"method\": \"Gene cloning, sequencing, promoter analysis, transcription start site mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing and structural characterization of SREBF2 gene with identification of functional promoter SRE-1 element\",\n      \"pmids\": [\"9070916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ATF6(N) (the cleaved nuclear form of ATF6) physically binds SREBP2(N) through its leucine-zipper domain, and the ATF6-SREBP2 complex on SRE-bound promoters recruits HDAC1, thereby suppressing SREBP2 transcriptional activity and reducing lipogenesis in liver cells. Glucose deprivation activates ATF6 and suppresses SREBP2-regulated transcription via this mechanism; blocking ATF6 cleavage by BiP/GRP78 reverses this inhibition.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, deletion mutagenesis, chromatin immunoprecipitation, overexpression in liver cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down and co-IP identifying direct interaction, ChIP showing complex at SRE, deletion mutagenesis mapping interaction domain, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"14765107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of either ABCG1 or ABCG4 in CNS cells increases the proteolytic processing of SREBP2 to its transcriptionally active form, inducing SREBP2 target genes and cholesterol synthesis; conversely, Abcg1 or Abcg4 knockout represses SREBP2 target gene expression in brain. Both ABCG1 and ABCG4 reside in RhoB-positive endocytic vesicle membranes and regulate intracellular sterol/cholesterol distribution upstream of SREBP2 activation.\",\n      \"method\": \"Abcg4 knockout mice, primary cell culture (astrocytes, microglia, neurons, macrophages), overexpression, cellular localization studies, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model plus overexpression with defined SREBP2 processing readout; single lab\",\n      \"pmids\": [\"17916878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SREBP2 directly binds to a sterol regulatory element (SRE) in the ABCA7 promoter and activates ABCA7 transcription in response to low cellular cholesterol, opposite to the LXR-driven regulation of ABCA1. Chromatin immunoprecipitation and promoter analysis identified the 9-bp SRE at positions −212 bp (mouse) and −179 bp (human) upstream of the ABCA7 transcription start site.\",\n      \"method\": \"Promoter analysis, SREBP2 forced expression/knockdown with siRNA, ChIP-implied promoter binding (promoter characterization with identified SRE)\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — promoter SRE identified and functional SREBP2 regulation confirmed by forced expression/siRNA, single lab, no direct ChIP for SREBP2 binding explicitly stated\",\n      \"pmids\": [\"16788211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-33a is encoded within intron 16 of the SREBF2 gene and is co-expressed with SREBP2 mRNA. miR-33 targets the 3′ UTR of ABCA1 and ABCG1, suppressing their translation and reducing LXR-dependent cholesterol efflux to ApoAI and serum; hepatic overexpression of miR-33 decreases ABCA1 protein and plasma HDL, while miR-33 silencing increases them.\",\n      \"method\": \"Co-expression analysis, 3′ UTR targeting assays, hepatic overexpression and silencing of miR-33 in vivo, cholesterol efflux assays, plasma HDL measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional in vivo and in vitro assays with gain- and loss-of-function, replicated across multiple labs (PMID 20566875 and 20732877)\",\n      \"pmids\": [\"20566875\", \"20732877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-33, encoded within SREBF2 intron, also inhibits translation of CPT1A, HADHB, and CROT (proteins involved in fatty acid β-oxidation), thereby reducing fatty acid degradation in addition to suppressing ABCA1-mediated cholesterol export.\",\n      \"method\": \"Luciferase reporter assays, miRNA overexpression, protein expression analysis, fatty acid oxidation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple target validation with functional readout, replicated in independent lab (PMID 20732877)\",\n      \"pmids\": [\"20732877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SREBP2 directly regulates NPC1L1 promoter activity and mRNA expression in a dose-dependent manner; chromatin immunoprecipitation confirmed that SREBP2 binds the NPC1L1 promoter in vivo in HuH7 cells. HNF1α also independently activates NPC1L1 transcription through a distinct HNF1 binding site.\",\n      \"method\": \"Correlation analysis in human liver samples, promoter-reporter assay, ChIP assay, SREBP2 and HNF1α overexpression in HuH7 cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming in vivo SREBP2 binding at NPC1L1 promoter, plus dose-dependent promoter reporter and mRNA assays; single lab\",\n      \"pmids\": [\"20460578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Akt kinase activation (via IGF-1 stimulation or rapalog-induced Akt heterodimerization) acutely activates SREBP2 within 1 hour; pharmacological or siRNA-mediated Akt inhibition blunts SREBP2 activation, establishing Akt as a direct upstream activator of SREBP2 processing/activation in cholesterol metabolism.\",\n      \"method\": \"IGF-1 stimulation, pharmacological Akt inhibitors, siRNA knockdown of Akt, rapalog heterodimerization system for specific Akt activation, SREBP2 activation assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological inhibition, siRNA, and inducible Akt activation system) converging on same result; single lab\",\n      \"pmids\": [\"22005015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LPS-activated TLR4-MyD88-NF-κB signaling increases SCAP expression and promotes its abnormal translocation from the ER to the Golgi, thereby activating the SCAP-SREBP2 pathway and upregulating LDLR and HMG-CoAR expression, leading to macrophage cholesterol accumulation and foam cell formation. Knockdown of MyD88 or SCAP, or blockade of IKK, each independently blocked this cross-talk.\",\n      \"method\": \"siRNA knockdown (MyD88, SCAP), IKK inhibitor, immunofluorescence/confocal microscopy for SCAP translocation, Western blot, RT-PCR, cholesterol measurement in macrophages\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNA targets and pharmacological inhibition with SCAP translocation imaging; single lab\",\n      \"pmids\": [\"23335792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Hepatic insulin receptor signaling is required for SREBP-2 induction in response to feeding and statins; liver insulin receptor knockout (LIRKO) mice show 40% decrease in Srebp-2 and 50–90% decrease in cholesterologenic genes, abolish the fasting-to-refeeding induction of SREBP-2, and lose the statin-induced SREBP-2 response. Ezetimibe (which alters intrahepatic cholesterol) restores SREBP-2 induction, suggesting insulin regulates SREBP-2 indirectly through cholesterol distribution.\",\n      \"method\": \"Liver-specific insulin receptor knockout mice, microarray, mRNA and protein expression analysis, pharmacological treatments (statins, ezetimibe)\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean liver-specific KO with defined molecular phenotype; single lab with multiple methods\",\n      \"pmids\": [\"24516236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Intestine-specific overexpression of active SREBP2 (driven by villin promoter in ISR2 transgenic mice) is sufficient to increase serum cholesterol in VLDL and LDL fractions and increase cholesterol and triglycerides in jejunum and liver, establishing that intestinal SREBP2 activation alone can drive hypercholesterolemia.\",\n      \"method\": \"Transgenic mouse model (villin-promoter driven active SREBP2), microarray of jejunal RNA, serum lipid and tissue lipid measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific transgenic model with defined lipid phenotype; single lab\",\n      \"pmids\": [\"24465397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SREBP-2 deficiency in mice causes embryonic lethality with defects in limb development and expression of morphogenic genes; surviving hypomorphic mice show reduced hepatic cholesterol, lower SREBP target gene expression, and near abolishment of hepatic Srebf1c transcripts, demonstrating that SREBP-2 is required for embryonic development and regulates SREBP-1c expression in a tissue-specific manner.\",\n      \"method\": \"SREBP-2 knockout and hypomorphic mouse generation, embryo analysis, gene expression analysis (mRNA, protein) in liver and adipose tissue\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO and hypomorphic mouse models with multiple defined phenotypic readouts across tissues; single lab but comprehensive genetic approach\",\n      \"pmids\": [\"26685326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FXR activation by agonists (GSK2324 or GW4064) induces Srebp-2 mRNA and precursor SREBP-2 protein via an FXR response element within intron 10 of Srebp-2, and co-induces miR-33 (suppressing ABCA1, NSF, CPT1); however, nuclear active SREBP-2 and its target genes are not induced because FXR simultaneously induces INSIG-2A, which blocks SCAP-mediated SREBP-2 processing. This uncouples miR-33 expression from mature SREBP-2 activity. FXR-dependent induction of both Srebp-2 and miR-33 requires SCAP (absent in Scap-/- mice).\",\n      \"method\": \"FXR agonist treatment, ChIP-seq (FXR response element identification), Scap-/- mice, mRNA and protein expression analysis, gene target analysis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq identification of FXR binding site, genetic knockout validation (Scap-/- mice), multiple molecular readouts; single lab\",\n      \"pmids\": [\"25593129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRTC2 (a transcription coactivator) regulates SREBP-2 transcription by interfering with FOXO1 recognition of insulin response element 1 (but not IRE2) in the SREBP-2 promoter, thereby inducing SREBP-2 and its target HMGCR to drive hepatic cholesterol synthesis. CRTC2 overexpression elevates liver cholesterol; SREBP-2 knockdown abolishes the CRTC2 effect on HMGCR.\",\n      \"method\": \"Adenovirus-mediated CRTC2 overexpression and CRTC2 knockout mice, in vivo HMGCR-luciferase imaging, promoter CRE/SRE mutation reporters, SREBP-2 siRNA rescue experiment\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo luciferase reporter with promoter mutagenesis, SREBP-2 KD rescue, and mouse models; single lab\",\n      \"pmids\": [\"28395113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"lop13 mice carry a spontaneous C3112T missense mutation (R1038C) in exon 18 of Srebf2, within its regulatory domain, causing nuclear cataracts, persistent skin wounds, and reduced cholesterol in brain, liver, and lens. Lack of complementation in Srebf2(lop13/GT) compound heterozygotes genetically confirms this hypomorphic Srebf2 mutation as causative, establishing Srebf2 as essential for lens and skin homeostasis.\",\n      \"method\": \"Linkage analysis, DNA sequencing, genetic complementation test (compound heterozygotes with gene-trap allele), gas chromatography for cholesterol measurement, histology\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic complementation test confirming causality, biochemical (GC) cholesterol measurements, multiple tissue phenotype analysis\",\n      \"pmids\": [\"21858719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNF5, an ER-anchored E3 ubiquitin ligase, mediates Lys-29-linked polyubiquitination of SCAP at Lys-305 (in cytosolic loop 2), which enhances the interaction between SCAP luminal loops 1 and 7 (a conformational change required for SREBP2 activation), thereby activating SREBP2 and promoting cholesterol biosynthesis. K305R SCAP variant fails to restore SREBP2 pathway in SCAP-deficient cells.\",\n      \"method\": \"RNF5 knockdown and overexpression in hepatoma cells, ubiquitination assays, mechanistic mutagenesis (K305R SCAP), interaction studies between SCAP luminal loops, rescue in SCAP-deficient cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination assays, site-specific mutagenesis, and complementation in deficient cell lines; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32054686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SREBP2 directly induces transcription of Transferrin (TF) in melanoma circulating tumor cells, thereby reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, and conferring resistance to ferroptosis inducers. Knockdown of TF impairs tumor formation, partially rescued by lipophilic antioxidants.\",\n      \"method\": \"Single-cell RNA analysis of patient CTCs, SREBP2-driven TF transcription assay, TF knockdown, ferroptosis rescue experiments with ferrostatin-1 and vitamin E\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional regulation shown with knockdown functional phenotype; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"33203734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Caspase-3 (CASP3) mediates cleavage of SREBP2 from the endoplasmic reticulum to promote cholesterol biosynthesis in hepatocellular carcinoma (HCC) cells, driving cancer stem cell expansion and resistance to sorafenib/lenvatinib treatment via activation of the sonic hedgehog signaling pathway. Loss of SREBP2 conferred sensitivity to tyrosine kinase inhibitors.\",\n      \"method\": \"RNA sequencing of drug-resistant patient-derived xenografts, SREBP2 loss-of-function (siRNA/CRISPR), caspase-3 cleavage assay, sonic hedgehog pathway analysis, xenograft mouse models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic cleavage assay with downstream pathway validation and in vivo xenograft; single lab\",\n      \"pmids\": [\"35767704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Qki-5 functions as a transcriptional co-activator of Srebp2 in oligodendrocytes to control transcription of cholesterol biosynthesis genes. Qki depletion in neural stem cells or OPCs results in impaired cholesterol biosynthesis and defective myelinogenesis (without blocking oligodendrocyte differentiation), and substantially reduces brain cholesterol concentration.\",\n      \"method\": \"Qki conditional knockout in neural stem cells or OPCs in mice, RNA-seq, cholesterol measurement, functional myelination assessment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific cellular readouts, co-activator role defined by genetic evidence; single lab\",\n      \"pmids\": [\"33942715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AAV2/5-mediated delivery of the transcriptionally active N-terminal fragment of human SREBP2 specifically to striatal astrocytes in R6/2 Huntington's disease mice activates cholesterol biosynthesis pathway genes, restores synaptic transmission, reverses Drd2 transcript decline, clears mutant huntingtin aggregates, and attenuates behavioral deficits, establishing that glial SREBP2 participates in HD brain pathogenesis.\",\n      \"method\": \"AAV2/5 gene therapy in R6/2 HD mice, electrophysiology (synaptic transmission), gene expression analysis, immunohistochemistry for huntingtin aggregates, behavioral tests\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with multiple defined readouts; single lab\",\n      \"pmids\": [\"33974044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Unspliced XBP1 (XBP1-u) colocalizes with SREBP2 and inhibits its ubiquitination/proteasomal degradation, thereby stabilizing SREBP2 and activating HMGCR transcription to promote cholesterol biosynthesis and tumorigenesis in HCC cells.\",\n      \"method\": \"Co-localization studies, ubiquitination assays, XBP1-u overexpression/knockdown, HMGCR expression analysis, tumor growth assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-localization and ubiquitination assay showing stabilization mechanism; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"35933495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SREBF2 directly binds the promoter region of STARD4 (a mitochondrial cholesterol trafficking protein) to promote its transcription, increasing mitochondrial cholesterol levels and inhibiting cytochrome c release, thereby conferring sorafenib resistance in HCC. SREBF2 knockdown decreases mitochondrial cholesterol and increases cytochrome c release; STARD4 overexpression reverses SREBF2 knockdown effects.\",\n      \"method\": \"ChIP showing SREBF2 binding to STARD4 promoter, SREBF2/STARD4 siRNA knockdown, mitochondrial cholesterol measurement, cytochrome c release assay, sorafenib-resistant xenograft models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP, functional rescue experiments, in vivo xenograft; single lab\",\n      \"pmids\": [\"35642354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP28, a deubiquitinating enzyme, binds mature SREBP2, deubiquitinates it, and stabilizes it, thereby increasing expression of mevalonate pathway enzymes and metabolic flux. USP28 silencing reduces SREBP2 protein levels and renders cancer cells sensitive to statin treatment (rescued by geranyl-geranyl pyrophosphate).\",\n      \"method\": \"USP28 siRNA/CRISPR deletion, deubiquitination assays, co-immunoprecipitation (USP28-SREBP2 interaction), metabolic flux analysis, tissue microarray analysis, SREBP2 CRISPR KO mouse tumor model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay, co-IP, in vivo tumor model, geranyl-geranyl pyrophosphate rescue; single lab\",\n      \"pmids\": [\"37202505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF11 interacts with SREBP2 protein and attenuates its ubiquitination-mediated degradation, thereby enhancing SREBP2 protein stability and accumulation and upregulating mevalonate pathway genes (HMGCR, FDFT1, SQLE, MSMO1) and free cholesterol to drive pancreatic cancer progression.\",\n      \"method\": \"Co-immunoprecipitation (KIF11-SREBP2), ubiquitination assay, SREBP2-dependent rescue experiments, xenograft mouse model\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP and ubiquitination assay; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"35619540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Caffeine increases hepatic ER Ca2+ levels, which blocks transcriptional activation (proteolytic processing) of SREBP2, thereby reducing PCSK9 expression and increasing LDLR expression and LDL-cholesterol clearance. ER Ca2+ is identified as a regulator of SREBP2 activation.\",\n      \"method\": \"Caffeine treatment in hepatic cells and human volunteers, ER Ca2+ measurement, SREBP2 processing assay, PCSK9 and LDLR expression analysis, analog development\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between ER Ca2+ and SREBP2 processing demonstrated in cells and confirmed in human volunteers; single lab\",\n      \"pmids\": [\"35140212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial HMGB1 regulates SREBP2 by prolonging its protein half-life (reducing its degradation rate); HMGB1 depletion reduces SREBP2 levels and consequently SR-BI expression, attenuating LDL transcytosis. Conversely, increased LDL causes SR-BI-dependent nuclear translocation of HMGB1. This HMGB1-SREBP2-SR-BI axis controls endothelial LDL transcytosis and atherosclerosis in vivo.\",\n      \"method\": \"siRNA knockdown in coronary artery endothelial cells, TIRF microscopy for LDL transcytosis, HMGB1 overexpression, SREBP2 half-life measurement, endothelial-specific HMGB1 KO mice, atherosclerosis assessment\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endothelial-specific KO mice with atherosclerosis readout, half-life measurements, TIRF microscopy; single lab\",\n      \"pmids\": [\"33054399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP2 overexpression in endothelial cells directly binds the promoter regions of mesenchymal genes (snai1, α-smooth muscle actin, vimentin, neural cadherin) and transactivates them, driving endothelial-to-mesenchymal transition. EC-specific SREBP2 transgenic mice show exacerbated vascular remodeling and mesenchymal transition after bleomycin-induced pulmonary fibrosis.\",\n      \"method\": \"SREBP2 overexpression transcriptomics, ChIP for promoter binding of mesenchymal genes, EC-specific transgenic SREBP2 mice, bleomycin pulmonary fibrosis model, epigenetic analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct promoter binding plus in vivo transgenic mouse model; single lab\",\n      \"pmids\": [\"34806652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PKCλ/ι (an atypical PKC) phosphorylates SCAP, promoting its degradation and thereby inhibiting SREBP2 processing and activation. PKCλ/ι deficiency in intestinal epithelial cells upregulates SREBP2 and cholesterol biosynthesis, driving mesenchymal/serrated colorectal cancer initiation.\",\n      \"method\": \"PKCλ/ι conditional knockout in intestinal epithelial cells, SCAP phosphorylation/degradation assay, SREBP2 processing assay, mouse serrated tumor model, human sample validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with SCAP phosphorylation mechanistic link to SREBP2; single lab\",\n      \"pmids\": [\"38092754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NBEAL1, a Golgi-associated BEACH domain protein, regulates SREBP2 processing by interacting with SCAP and PAQR3, modulating LDLR expression. Reduced NBEAL1 expression leads to downregulation of LDLR and is associated with increased coronary artery disease risk.\",\n      \"method\": \"NBEAL1 knockdown/overexpression, co-immunoprecipitation (NBEAL1-SCAP-PAQR3 interaction), SREBP2 processing assay, LDLR expression analysis, human genetic association (eQTL)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP identifying protein interaction and SREBP2 processing modulation; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"32161285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SREBP2 directly binds the SRBEF2 (own gene) promoter SRE-1 element and also directly regulates SQLE gene promoter (through two newly identified SP1 and SREBF2 binding sites). OSBPL2 deletion inhibits AMPK signaling, allowing SP1 and SREBF2 to enter the nucleus and upregulate SQLE, increasing intracellular cholesterol and cholesteryl ester accumulation.\",\n      \"method\": \"CRISPR/Cas9 OSBPL2 knockout, RNA-seq, dual-luciferase reporter assay for SQLE promoter with transcription factor binding site mapping, AMPK signaling analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase reporter assay with site identification and AMPK pathway functional analysis; single lab\",\n      \"pmids\": [\"31356817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Estrogen (E2) stimulates SREBP2 transcription in hepatic cells (HepG2, HuH-7) via a functional estrogen response element (ERE) in the SREBP2 promoter, to which ERα specifically binds; this is blocked by ERα antagonist. E2-driven SREBP2 induction increases HMGCR and LDLR expression and lipid secretion.\",\n      \"method\": \"Luciferase reporter assay with ERE and mutated ERE constructs, ChIP analysis confirming ERα binding at SREBP2 promoter, ERα antagonist treatment, RT-PCR and immunofluorescence\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming in vivo ERα binding, luciferase reporter with mutagenesis, receptor antagonist; single lab\",\n      \"pmids\": [\"31827541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In neurons challenged with oligomeric Aβ42, SREBP2 activation is reduced because Aβ42 impairs Akt phosphorylation, which is required for SREBP2 transport from the ER to the Golgi (but does not affect enzymatic cleavage per se). Constitutively active Akt overexpression prevents Aβ42-induced SREBP2 inhibition and the downstream block of cholesterol synthesis and protein prenylation.\",\n      \"method\": \"Multiple neuronal cell types, oAβ42 treatment, Akt phosphorylation assay, SREBP2 activation assay, constitutively active Akt overexpression rescue, TgCRND8 AD mouse brain analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic rescue with constitutively active Akt, in vivo AD mouse validation, multiple cell types; single lab\",\n      \"pmids\": [\"29122977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TGF-β induces SREBP-2 and HMGCR expression in chondrocytes via integrin αV (ITGAV) and PI3K/Akt signaling. Smad3 interacts with SREBP-2. A functional SNP (1784G>C) in SREBP-2 causes upregulation of IL-1β and MMP-13 in chondrocytes. Integrin inhibition with cyclo-RGDFV peptide downregulates SREBP-2, HMGCR, phospho-PI3K, and MMP-13 and upregulates aggrecan.\",\n      \"method\": \"TGF-β treatment of normal chondrocytes, ITGAV/PI3K/Akt pathway analysis, Smad3-SREBP-2 interaction (implied), cyclo-RGDFV peptide treatment, SREBP-2 plasmid transfection with functional readouts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell-based experiments with pathway inhibitors; interaction between Smad3 and SREBP2 not explicitly confirmed by Co-IP in abstract; single lab\",\n      \"pmids\": [\"22662110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APP α-cleavage product (APPsα ectodomain) acts as a positive regulator of SREBP2 signaling in astrocytic, hepatic, and fibroblast cells, increasing SRE-dependent gene expression (~30%), cholesterol biosynthesis, and LDL receptor levels. The β-cleaved ectodomain represses SRE-dependent gene expression (~30%), establishing opposing paracrine regulators of SREBP2. In cholesterol-loaded cells (where β-cleavage dominates), this creates a feedback loop reducing cholesterol synthesis.\",\n      \"method\": \"APP cleavage product treatment in multiple human cell lines (U251MG, HepG2, fibroblasts), SRE-reporter assay, cholesterol biosynthesis and LDLR measurement, β-cleavage inhibitor experiments, patient fibroblast analysis\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types and genetic conditions with SRE reporter, mechanistic rescue experiments; single lab\",\n      \"pmids\": [\"24249638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP2 directly binds the promoter region of YAP and transactivates it; uric acid/monosodium urate-induced SREBP2 in endothelial cells drives YAP signaling and pro-inflammatory gene expression. SREBP2 siRNA knockdown partially abolishes UA/MSU-induced YAP activity and monocyte adhesion; endothelial SREBP2 transgenic mice show activated YAP signaling.\",\n      \"method\": \"SREBP2 siRNA, adenovirus-SREBP2 overexpression with RNA-seq, SREBP2 endothelial transgenic mice, pharmacological SREBP2 inhibitor (betulin), promoter binding assay (implied), hyperuricemia mouse model\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic and pharmacological models with RNA-seq, siRNA rescue; YAP as direct SREBP2 transcriptional target established by gain-of-function; single lab\",\n      \"pmids\": [\"33977576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Melanoma-derived lactate activates SREBP2 in tumor-infiltrating conventional dendritic cells, driving their transformation into mature regulatory DCs (mregDCs) via the mevalonate biosynthetic pathway. DC-specific genetic silencing or pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63 was identified as a surface marker for mregDCs.\",\n      \"method\": \"DC-specific SREBP2 genetic silencing, pharmacological SREBP2 inhibition, transcriptional and metabolic studies, lactate treatment of DCs, T cell activation assays, in vivo melanoma models, human sentinel lymph node analysis\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DC-specific genetic KD with defined immune phenotype and in vivo tumor suppression; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38728412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALOX15B-mediated lipid peroxidation activates ERK1/2 in macrophages, which in turn increases SREBP2 nuclear abundance and activity, controlling cholesterol biosynthesis. ALOX15B silencing reduces ERK1/2 activation and nuclear SREBP2, suppressing sterol biosynthetic intermediates (desmosterol, lathosterol) and making macrophages refractory to NPC1 inhibition-induced SREBP2 activation.\",\n      \"method\": \"ALOX15B siRNA in primary human macrophages, global transcriptome analysis, immunofluorescence for nuclear SREBP2, ERK1/2 inhibition, sterol biosynthetic intermediate measurement by mass spectrometry\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary human macrophages with transcriptome plus targeted biochemical validation of ERK1/2-SREBP2 axis; single lab\",\n      \"pmids\": [\"38581859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX10 (sorting nexin 10) interacts with SCAP, and SNX10 deletion promotes dissociation of ERLIN2 from SCAP, enhancing SREBP2 activation and increasing intracellular cholesterol biosynthesis in intestinal stem cells, promoting their stemness. SNX10 conditional knockout in intestinal epithelial cells or ISCs promotes mucosal repair.\",\n      \"method\": \"SNX10 conditional knockout mice, ERLIN2-SCAP interaction analysis, SREBP2 activation assay, intracellular cholesterol measurement, ISC stemness assays, SNX10 small-molecule inhibitor (DC-SX029)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined SCAP-ERLIN2 dissociation mechanism and SREBP2 activation readout; single lab\",\n      \"pmids\": [\"37647408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear SREBP2 (nSREBP2) forms phase-separated condensates in the nucleus through its amino-terminal intrinsically disordered region (IDR). These condensates co-localize with transcription coactivators, partly on superenhancers, to activate lipogenic gene transcription. A conserved phenylalanine-to-alanine substitution in the IDR abolishes condensate formation and reduces transcriptional activity; fusion with a phase-separation-driving FUS-IDR rescues activity. Knock-in of this mutation in male mice impairs feeding-induced nSREBP2 activity and lowers hepatic and circulating cholesterol.\",\n      \"method\": \"Phase separation assays (condensate formation), IDR mutagenesis (Phe→Ala), FUS-IDR fusion rescue, ChIP-seq on superenhancers, knock-in mouse model, cholesterol measurement in vivo\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phase separation plus mutagenesis rescue, FUS-IDR fusion control, and in vivo knock-in mouse with functional metabolic readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40394324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LPS increases SREBF2 expression via the TLR4/JNK/c-Jun signaling pathway, and simultaneously suppresses UBE2I-mediated SREBF2 sumoylation to enhance its transcriptional activity, resulting in increased intracellular cholesterol and ER stress (Bax upregulation) in portal vein endothelial cells.\",\n      \"method\": \"LPS treatment of endothelial cells, TLR4/JNK/c-Jun pathway analysis, sumoylation assay (UBE2I knockdown), SREBF2 expression and transcriptional activity assays, ER stress markers\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway and sumoylation assays in single cell model; limited mechanistic depth in abstract; single lab\",\n      \"pmids\": [\"33677747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Parkin expression level positively correlates with neuronal lipoprotein lipase (LPL) protein level and activity through SREBP2 as mediator; SREBP2 genetic ablation abolishes Parkin's effect on LPL expression. The Parkin-SREBP2-LPL pathway regulates intracellular lipid droplet formation and is upregulated by PD-linked oxidative stress (rotenone).\",\n      \"method\": \"Human neuroblastoma cell line and Parkin knockout mouse model, LPL activity assay, SREBP2 genetic ablation, lipid droplet assay, rotenone oxidative stress treatment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with SREBP2 ablation rescue defining pathway position; single lab\",\n      \"pmids\": [\"36519761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SREBP2 directly regulates LDLR transcription by binding its promoter; SREBP2 also indirectly regulates LDLR by increasing transcription of lncRNA LDLR-AS in fish hepatocytes. LDLR-AS functions as an RNA scaffold recruiting hnRNPR to the 5′ UTR of LDLR mRNA, stabilizing LDLR mRNA post-transcriptionally.\",\n      \"method\": \"SREBP2 knockdown, ChIP/reporter assay for LDLR promoter binding, LDLR-AS knockdown, RNA immunoprecipitation for hnRNPR binding, mRNA stability assay, triglyceride accumulation measurement (fish model)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — fish (non-mammalian) model; SREBP2 direct promoter binding implied but mechanistic details limited in abstract; single lab\",\n      \"pmids\": [\"35811843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP2 binds to the promoter region of NLRC4 and activates its transcription in keratinocytes; LCN2 signaling through SREBP2 drives NLRC4-mediated inflammation in psoriasis. Suppressing SREBP2 in mice attenuated NLRC4 signaling and psoriasis-like dermatitis.\",\n      \"method\": \"ChIP showing SREBP2 binding to NLRC4 promoter, SREBP2 knockdown in mice, LCN2/24p3R silencing in psoriasis mouse model, in vitro keratinocyte assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct SREBP2-NLRC4 promoter binding with in vivo mouse model; single lab\",\n      \"pmids\": [\"35120997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZIKV infection increases recruitment of SREBP2 transcription factors to lipid gene promoters; pharmacological inhibition or genetic silencing of SREBP2 suppresses ZIKV infection of human dendritic cells, establishing SREBP2-activated lipid gene transcription as a mechanism exploited for viral replication.\",\n      \"method\": \"Genomics profiling of ZIKV-infected vs uninfected primary human DCs, ChIP for SREBP2 at lipid gene promoters, pharmacological SREBP2 inhibition, SREBP2 siRNA knockdown, ZIKV infectivity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing SREBP2 recruitment, genetic and pharmacological loss-of-function with viral infectivity readout; single lab\",\n      \"pmids\": [\"36097162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SREBP-2 pathway activity is required for the cytotoxicity of C. difficile toxins A and B; SREBP-2 regulates membrane cholesterol content, which is necessary for toxin pore formation in endosomal membranes and translocation of the glucosyltransferase domain. Pharmacological SREBP-2 pathway inhibition (PF-429242, 25-hydroxycholesterol, simvastatin) or SREBP-2 pathway-deficient cells protected against toxin intoxication; this protection was bypassed when the toxin's enzyme domain was delivered independently of pore formation.\",\n      \"method\": \"SREBP-2 pathway inhibitors (pharmacological and genetic), toxin B pore formation assay, anthrax protective antigen-mediated enzyme delivery (mechanistic bypass), cell viability assays\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic bypass experiment with anthrax PA delivery confirming pore formation dependence, multiple pharmacological inhibitors and pathway-deficient cells; single lab\",\n      \"pmids\": [\"30592645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Elaidate (industrial trans fatty acid) activates SREBP2 via the SCAP-SREBP2 axis in hepatocytes by lowering intracellular free cholesterol levels, inducing cholesterol biosynthesis. This effect is SCAP-dependent but independent of liver-X receptor and UBXD8. Exogenous cholesterol represses, and elaidate attenuates, this anti-cholesterogenic feedback.\",\n      \"method\": \"Transcriptomics of hepatoma cells treated with elaidate vs oleate/palmitate, SCAP-dependent knockdown experiments, intracellular free cholesterol measurement, SREBP2 activity assay, diet-fed mouse model\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SCAP-dependent mechanism with gene knockdown and cholesterol measurement, plus in vivo mouse diet model; single lab\",\n      \"pmids\": [\"31327168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In MFP2 (multifunctional protein 2, peroxisomal β-oxidation) knockout mice, PPAR-α activation by endogenous ligands (from accumulated peroxisomal substrates) leads to upregulation of SREBP2 and HMGCR; in MFP2/PPAR-α double knockout mice, SREBP2 and HMGCR upregulations are markedly attenuated, demonstrating a PPAR-α-dependent pathway for SREBP2 induction.\",\n      \"method\": \"MFP2 KO and MFP2/PPARα double KO mice, real-time PCR, gene expression profiling, cholesterol biosynthesis rate measurement\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double KO epistasis establishing PPAR-α dependence of SREBP2 induction; single lab\",\n      \"pmids\": [\"18773970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Irisin activates AMPK in hepatocytes, which inhibits SREBP2 transcription and nuclear translocation, reducing hepatic cholesterol synthesis. AMPKα1 siRNA or compound C (AMPK inhibitor) blocks irisin-induced changes in SREBP2 and cholesterol levels, establishing AMPK as a required mediator between irisin and SREBP2.\",\n      \"method\": \"Irisin infusion in DIO mice, primary hepatocyte treatment, AMPK activation/inhibition (compound C, AMPKα1 siRNA), SREBP2 nuclear translocation assay, cholesterol measurement\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA) and pharmacological AMPK inhibition with SREBP2 nuclear translocation assay in vivo and in vitro; single lab\",\n      \"pmids\": [\"27211556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SREBP2 directly induces transcription of PCSK9 via the sterol regulatory element in its promoter; caffeine blocks this by increasing ER Ca2+. PXR activation increases proteolytic activation of SREBP2 (SCAP-mediated), driving widespread induction of cholesterol synthesis genes and PCSK9 in mice and humans.\",\n      \"method\": \"PXR ligand (rifampicin) treatment in humans and mice, NMR metabolomics, PXR KO mice, cholesterol synthesis intermediate measurement (lathosterol ratio), PCSK9 plasma measurement\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human crossover study plus PXR KO mice with cholesterol synthesis intermediates and PCSK9 as readouts; single lab with clinical confirmation\",\n      \"pmids\": [\"33687065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SREBP2 (encoded by SREBF2) is a membrane-bound bHLH-leucine zipper transcription factor that, under cholesterol-deficient conditions, undergoes SCAP-mediated ER-to-Golgi transport and proteolytic cleavage to release its N-terminal domain, which enters the nucleus to activate sterol-responsive target genes (LDLR, HMGCR, PCSK9, STARD4, NPC1L1, and others); nuclear SREBP2 activity is enhanced by phase-separated condensate formation via its N-terminal intrinsically disordered region; upstream regulators include Akt (required for ER-to-Golgi transport), AMPK (inhibitory), RNF5 (E3 ligase ubiquitinating SCAP to promote activation), USP28 (deubiquitinase stabilizing mature SREBP2), ATF6 (which binds SREBP2 via its leucine-zipper domain and recruits HDAC1 to suppress activity), FXR (which induces Srebp2 transcription but simultaneously induces INSIG-2A to block processing), and ER Ca2+ (required for processing); the SREBF2 locus is bifunctional, also encoding intronic miR-33a, which post-transcriptionally suppresses ABCA1, ABCG1, and fatty acid β-oxidation enzymes (CPT1A, HADHB, CROT) to complement SREBP2-driven lipid anabolism; SREBP2 plays essential roles in embryonic development, myelinogenesis (as a Qki co-activator in oligodendrocytes), neuronal cholesterol homeostasis, immune cell function (including tolerogenic DC differentiation driven by tumor lactate), and is co-opted in multiple cancers through mechanisms including caspase-3-mediated cleavage and deubiquitination by USP28.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SREBF2 encodes SREBP2, a membrane-bound basic helix-loop-helix-leucine zipper transcription factor that serves as a master regulator of cholesterol homeostasis: under sterol-poor conditions a sterol-regulated protease cleaves the membrane-attached precursor to release its N-terminal bHLH-Zip domain, which enters the nucleus to transactivate sterol-responsive genes [#0]. SREBP2 is subject to negative feedback through a perfect sterol regulatory element (SRE-1) in its own promoter, providing autoregulatory control by sterol levels [#1, #30]. Its direct transcriptional target repertoire spans cholesterol uptake and synthesis (LDLR, HMGCR, PCSK9, NPC1L1, SQLE, the lipid transporters ABCA7 and STARD4) [#4, #7, #22, #30, #49], and the locus is bifunctional, co-expressing intronic miR-33a that post-transcriptionally suppresses ABCA1, ABCG1, and fatty-acid β-oxidation enzymes (CPT1A, HADHB, CROT), coupling SREBP2-driven anabolism to repression of cholesterol efflux and lipid catabolism [#5, #6]. SREBP2 activation is gated at the proteolytic-processing step by the SCAP machinery, which integrates numerous inputs: Akt is required for ER-to-Golgi transport of SREBP2 [#8, #32], RNF5-mediated ubiquitination of SCAP promotes the conformational change needed for activation [#16], AMPK signaling is inhibitory [#48], ER Ca2+ is required for processing [#25], and the mature nuclear protein is stabilized against ubiquitin-dependent degradation by USP28 [#23]. Nuclear SREBP2 acts through phase-separated condensates formed by its N-terminal intrinsically disordered region, which co-localize with coactivators at superenhancers to drive lipogenic transcription; abolishing condensate formation lowers transcriptional activity and circulating cholesterol [#39]. SREBP2 is essential for embryonic development and tissue homeostasis—its loss causes embryonic lethality and limb defects, and a hypomorphic point mutation produces nuclear cataracts and skin defects with reduced tissue cholesterol [#12, #15]—and it has dedicated roles in oligodendrocyte myelinogenesis as a Qki co-activated regulator of brain cholesterol synthesis [#19]. Beyond canonical lipid metabolism, SREBP2 directly transactivates non-lipogenic targets to drive disease programs, including mesenchymal genes in endothelial-to-mesenchymal transition [#27], NLRC4 in keratinocyte inflammation [#43], and transferrin to suppress ferroptosis [#17], and is co-opted across cancers and pathogens through caspase-3-mediated cleavage and stabilization [#18, #44, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding mechanistic model: SREBP2 is a membrane-tethered bHLH-Zip transcription factor activated by sterol-regulated proteolysis that liberates a nuclear transcriptional domain.\",\n      \"evidence\": \"Gene cloning, FISH mapping, and structural characterization defining domain architecture and proteolytic activation\",\n      \"pmids\": [\"7759101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the regulated protease and the full upstream transport machinery not resolved here\", \"Genome-wide target spectrum unknown at this stage\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the autoregulatory logic of the pathway by locating a functional SRE-1 in the SREBF2 promoter, showing the transcription factor regulates its own gene by sterol levels.\",\n      \"evidence\": \"Genomic cloning, sequencing, and promoter analysis of the 19-exon SREBF2 locus\",\n      \"pmids\": [\"9070916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish quantitative feedback dynamics in vivo\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a direct protein-protein brake on SREBP2 output: ATF6(N) binds SREBP2(N) via its leucine zipper and recruits HDAC1 at SRE promoters to suppress lipogenesis, linking the unfolded protein response to cholesterol synthesis.\",\n      \"evidence\": \"Reciprocal GST pull-down/co-IP, deletion mapping, and ChIP in liver cells under glucose deprivation\",\n      \"pmids\": [\"14765107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and genomic breadth of ATF6-SREBP2 co-occupancy not defined\", \"In vivo physiological contribution not quantified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Expanded the direct target set to lipid transporters, showing SREBP2 binds SREs in ABCA7 (opposite to LXR) and that ABCG1/ABCG4-controlled sterol distribution feeds back on SREBP2 processing.\",\n      \"evidence\": \"Promoter/SRE analysis with forced expression and siRNA (ABCA7); Abcg4 knockout plus overexpression with SREBP2 processing readout (CNS cells)\",\n      \"pmids\": [\"16788211\", \"17916878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ChIP for SREBP2 at ABCA7 not explicitly shown\", \"Tissue specificity of these regulatory relationships incompletely mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed the SREBF2 locus as bifunctional: intronic miR-33a is co-expressed with SREBP2 and suppresses ABCA1/ABCG1 and β-oxidation enzymes, coordinating anabolic transcription with repression of efflux and catabolism.\",\n      \"evidence\": \"3' UTR/luciferase target validation, hepatic gain/loss of function in vivo, cholesterol efflux and HDL measurement; replicated across labs\",\n      \"pmids\": [\"20566875\", \"20732877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of miR-33 vs SREBP2 protein to net lipid phenotype not partitioned\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended direct transcriptional targeting to the intestinal sterol absorption transporter NPC1L1, confirmed by in vivo promoter occupancy.\",\n      \"evidence\": \"Promoter-reporter, ChIP in HuH7 cells, and dose-dependent overexpression\",\n      \"pmids\": [\"20460578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological impact on dietary cholesterol absorption not tested genetically\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed Akt kinase as a direct upstream activator acting on the processing/transport step, linking growth-factor signaling to acute SREBP2 activation.\",\n      \"evidence\": \"IGF-1 stimulation, Akt inhibitors, siRNA, and rapalog-inducible Akt heterodimerization with SREBP2 activation assay\",\n      \"pmids\": [\"22005015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation substrate within the transport machinery not pinpointed in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established physiological in vivo control nodes: hepatic insulin receptor signaling is required for feeding- and statin-induced SREBP2 (likely via cholesterol distribution), and intestinal SREBP2 activation alone is sufficient to cause hypercholesterolemia.\",\n      \"evidence\": \"Liver-specific insulin receptor knockout with ezetimibe rescue; villin-promoter active-SREBP2 transgenic mice with lipid phenotyping\",\n      \"pmids\": [\"24516236\", \"24465397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between insulin and intracellular cholesterol redistribution remains indirect\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated SREBP2 is essential for embryonic development and that its activity can be uncoupled from its transcription, since FXR induces Srebp2 mRNA and miR-33 yet blocks mature protein production by inducing INSIG-2A.\",\n      \"evidence\": \"SREBP2 knockout/hypomorphic mice with embryo analysis; FXR agonists, ChIP-seq FXR response element, and Scap-/- validation\",\n      \"pmids\": [\"26685326\", \"25593129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Developmental targets of SREBP2 driving limb/morphogenic defects not identified\", \"Physiological settings where the transcription/processing uncoupling dominates not delineated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetically confirmed SREBP2 as essential for tissue homeostasis: a hypomorphic regulatory-domain missense mutation causes cataracts, skin defects, and reduced tissue cholesterol, with causality proven by complementation testing.\",\n      \"evidence\": \"lop13 spontaneous R1038C mutant, linkage, complementation with gene-trap allele, GC cholesterol measurement\",\n      \"pmids\": [\"21858719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular consequence of the R1038C regulatory-domain mutation on processing not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how SCAP conformational activation is post-translationally licensed and how mature SREBP2 abundance is controlled, identifying RNF5-mediated SCAP ubiquitination and USP28 deubiquitination of nuclear SREBP2 as opposing controls.\",\n      \"evidence\": \"RNF5 ubiquitination assays and K305R SCAP rescue; USP28 co-IP, deubiquitination assays, and statin-sensitivity rescue with GGPP\",\n      \"pmids\": [\"32054686\", \"37202505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counteracting E3 ligase for mature SREBP2 not defined\", \"Signals that toggle RNF5/USP28 activity not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered non-canonical SREBP2 functions beyond lipid synthesis, including direct transactivation of transferrin to suppress ferroptosis in metastatic melanoma and caspase-3-mediated cleavage driving cancer stemness and drug resistance.\",\n      \"evidence\": \"Single-cell CTC analysis with TF knockdown and ferroptosis rescue; caspase-3 cleavage assay, SREBP2 loss-of-function, and xenografts in HCC\",\n      \"pmids\": [\"33203734\", \"35767704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of caspase-3 cleavage as a physiological activation route unclear\", \"Whether TF is a canonical SRE-driven target not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a tissue-specific developmental role through co-activator partnership, with Qki-5 acting as a transcriptional co-activator of Srebp2 to drive oligodendrocyte cholesterol synthesis and myelinogenesis.\",\n      \"evidence\": \"Qki conditional knockout in neural stem cells/OPCs with RNA-seq, cholesterol measurement, and myelination assays\",\n      \"pmids\": [\"33942715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical Qki-SREBP2 interaction interface not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SREBP2 directly transactivates non-lipogenic disease-driver genes, binding promoters of mesenchymal genes (EndMT) and YAP and NLRC4 in inflammation.\",\n      \"evidence\": \"ChIP for promoter binding, EC-specific transgenic mice, and siRNA rescue across fibrosis, hyperuricemia, and psoriasis models\",\n      \"pmids\": [\"34806652\", \"33977576\", \"35120997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these targets require canonical SREs or alternative motifs not resolved\", \"Sterol-dependence of these programs unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ER Ca2+ as a required input to processing and mapped additional protein stabilizers (XBP1-u, KIF11) and a direct mitochondrial-cholesterol target (STARD4), explaining drug-resistance phenotypes in cancer.\",\n      \"evidence\": \"Caffeine/ER-Ca2+ manipulation with processing and PCSK9/LDLR readout; co-localization/ubiquitination assays; ChIP at STARD4 promoter with rescue\",\n      \"pmids\": [\"35140212\", \"35933495\", \"35642354\", \"35619540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KIF11-SREBP2 interaction rests on single co-IP without reciprocal validation\", \"Mechanism by which ER Ca2+ gates SCAP-mediated processing not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Continued mapping of upstream SCAP-level regulators, adding PKCλ/ι phosphorylation-driven SCAP degradation and SNX10-controlled ERLIN2-SCAP dissociation as brakes whose loss drives intestinal tumor/stem-cell programs.\",\n      \"evidence\": \"Conditional knockouts in intestinal epithelium with SCAP phosphorylation/degradation and SREBP2 processing assays\",\n      \"pmids\": [\"38092754\", \"37647408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay among RNF5, PKCλ/ι, SNX10, and ERLIN2 at SCAP not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SREBP2 to tumor immune evasion and lipid-peroxidation signaling, showing tumor lactate activates SREBP2 to generate immunosuppressive regulatory dendritic cells and that ALOX15B-ERK1/2 raises nuclear SREBP2 in macrophages.\",\n      \"evidence\": \"DC-specific SREBP2 silencing with T-cell and tumor readouts; ALOX15B siRNA in primary human macrophages with sterol-intermediate mass spectrometry\",\n      \"pmids\": [\"38728412\", \"38581859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SREBP2's immunosuppressive role is purely mevalonate-dependent not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a biophysical mechanism for nuclear SREBP2 transactivation, showing its N-terminal IDR drives phase-separated condensates at superenhancers required for full lipogenic transcription in vivo.\",\n      \"evidence\": \"Phase-separation assays, IDR Phe→Ala mutagenesis with FUS-IDR rescue, ChIP-seq, and knock-in mouse with cholesterol phenotyping\",\n      \"pmids\": [\"40394324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivators recruited into condensates not exhaustively identified\", \"How sterol signaling tunes condensate dynamics unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many upstream SCAP-level regulators, nuclear stabilizers, and condensate dynamics are integrated into a unified quantitative model of context-specific SREBP2 output, and which mechanisms govern its expanding non-lipogenic target programs, remain open.\",\n      \"evidence\": \"No single study in the corpus integrates these layers mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking processing-level and stability-level control\", \"Sterol-dependence of non-canonical targets unresolved\", \"Structural basis of target selection between lipogenic and non-lipogenic promoters unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 4, 7, 22, 27, 30, 43, 49]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 7, 22, 27, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 18, 25, 32]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 39, 48]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [9, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5, 6, 30, 46, 49]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 4, 7, 22, 27, 30, 43]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 25, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SCAP\", \"ATF6\", \"USP28\", \"RNF5\", \"QKI\", \"XBP1\", \"KIF11\", \"AKT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}