{"gene":"HMGCR","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2020,"finding":"USP20 deubiquitylase stabilizes HMGCR in the fed state: mTORC1 phosphorylates USP20 at S132 and S134 in response to postprandial insulin/glucose, which recruits USP20 to the HMGCR complex and antagonizes HMGCR ubiquitin-dependent degradation, thereby increasing cholesterol biosynthesis.","method":"Liver-specific Usp20 knockout mice, USP20(S132A/S134A) knock-in mice, co-immunoprecipitation, in vivo and in vitro ubiquitylation assays, rescue with constitutively stable HMGCR(K248R)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal genetic and biochemical methods in vivo and in vitro, causal rescue experiment","pmids":["33177714"],"is_preprint":false},{"year":2019,"finding":"Lanosterol is the bona fide endogenous sterol intermediate that specifically stimulates HMGCR degradation; other C4-dimethylated sterol intermediates (24,25-dihydrolanosterol, FFMAS, TMAS, dihydro-TMAS) regulate both HMGCR degradation and SREBP-2 cleavage inhibition, as demonstrated by CRISPR/Cas9 deletion of individual mevalonate pathway enzymes and lipidomics.","method":"CRISPR/Cas9 gene deletion of mevalonate pathway enzymes, lipidomics, immunoblot for HMGCR and SREBP-2 status in HeLa cells expressing mevalonate transporter","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — systematic CRISPR knockouts combined with lipidomics and functional readouts in a single rigorous study","pmids":["31455613"],"is_preprint":false},{"year":2017,"finding":"UBXD8 is an essential mediator of sterol-stimulated proteasomal degradation of HMGCR: it is required for dislocation of ubiquitylated HMGCR from the ER membrane en route to proteasomal degradation, a function dependent on its UBX domain.","method":"Haploid mammalian genetic screen with CRISPR/Cas9-tagged endogenous HMGCR-mNeon, UBXD8 ablation in multiple cell types, domain mutagenesis","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased genetic screen confirmed by mechanistic domain studies in multiple cell types","pmids":["28882874"],"is_preprint":false},{"year":2018,"finding":"UBE2G2 is the E2 ubiquitin-conjugating enzyme specifically required for sterol-stimulated ubiquitylation and degradation of HMGCR (distinct from SQLE which uses UBE2J2), identified by CRISPR/Cas9 screen of ERAD-associated E2 enzymes.","method":"CRISPR/Cas9-based E2 enzyme screen, ubiquitylation assays, HMGCR protein stability measurements in multiple human cell types","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 1-2 — systematic CRISPR screen with enzymatic activity validation across multiple cell types","pmids":["30658189"],"is_preprint":false},{"year":2008,"finding":"An intronic SNP (rs3846662) in HMGCR modulates alternative splicing of exon 13; the minor allele is associated with up to 2.2-fold lower expression of the exon-13-skipped isoform, and the alternative splice variant lacking exon 13 cannot restore HMGCR enzymatic activity in HMGCR-deficient UT-2 cells.","method":"Minigene transfection splicing assay, in vitro complementation assay in HMGCR-deficient UT-2 cells, human lymphoblastoid cell lines","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 — functional splicing assay plus enzymatic complementation assay, replicated across populations","pmids":["18802019"],"is_preprint":false},{"year":2013,"finding":"HNRNPA1 directly binds the rs3846662 SNP site in HMGCR pre-mRNA and promotes exon 13 skipping in an allele-dependent manner; HNRNPA1 overexpression also specifically stabilizes the exon-13-skipped HMGCR transcript, reduces HMGCR enzyme activity, enhances LDL-C uptake, and increases cellular apoB.","method":"HNRNPA1 RNA-binding assay, HNRNPA1 overexpression, HMGCR enzyme activity assay, LDL uptake assay, hepatoma cell lines","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding demonstrated, multiple functional readouts, consistent with two independent clinical trial datasets","pmids":["24001602"],"is_preprint":false},{"year":2024,"finding":"BRCC36 deubiquitinates HMGCR in a DUB activity-dependent manner; HMGCR localization shifts from mitochondria during ferroptosis to the endoplasmic reticulum during pyroptosis, and BRCC36-mediated HMGCR stabilization inhibits ferroptosis while promoting pyroptosis.","method":"Co-immunoprecipitation, deubiquitylation assay, immunofluorescence subcellular localization, BRCC36 inhibitor (thiolutin), cell death assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus pharmacological inhibitor, single lab","pmids":["38178583"],"is_preprint":false},{"year":2023,"finding":"SIAH1, an E3 ubiquitin ligase, ubiquitinates HMGCR, thereby modulating cholesterol synthesis and efflux protein activity in lung cancer cells; SIAH1 overexpression suppresses tumor growth and enhances cisplatin sensitivity in vivo.","method":"Co-immunoprecipitation, ubiquitylation assay, HMGCR knockdown and SIAH1 overexpression in vitro and xenograft models","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 — biochemical ubiquitylation assay supported by in vivo xenograft, single lab","pmids":["37062828"],"is_preprint":false},{"year":2017,"finding":"SREBP-2 activates human HMGCR transcription via two sterol-regulatory elements (SREs) and one NF-Y site in the HMGCR promoter; HMGCR expression is highly activated only when SREBP-2 levels are very high, unlike LDLR which responds at lower SREBP-2 levels.","method":"Luciferase reporter assays with SRE/NF-Y mutant library, electrophoretic mobility shift assay (EMSA), ChIP-PCR","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (reporter assay, EMSA, ChIP) in one study","pmids":["28342963"],"is_preprint":false},{"year":2015,"finding":"An estrogen response element (ERE) in the HMGCR promoter mediates estradiol-dependent upregulation of HMGCR expression in hepatocytes, leading to increased cholesterol synthesis.","method":"Promoter ERE identification, E2 treatment of HepG2 cells and mouse fetal hepatocytes, in vivo ovarian stimulation mouse model with HMGCR expression measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — ERE identified with in vitro and in vivo concordance, single lab","pmids":["25961186"],"is_preprint":false},{"year":2012,"finding":"HMGCR pathway activity in zebrafish is required for developmental cerebral vascular stability through protein geranylgeranylation: HMGCR inhibition causes cerebral hemorrhage rescued by geranylgeranyl pyrophosphate (GGPP) supplementation; depletion of GGTase-I (β-subunit) mimics HMGCR loss-of-function and reduces endothelial Cdc42 expression.","method":"Pharmacological HMGCR inhibition, genetic morpholino knockdown of GGTase-I β-subunit, GGPP rescue in zebrafish, live imaging","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — pharmacological and genetic approaches with specific pathway rescue in vivo","pmids":["23206891"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, Hmgcr expression in the corpus allatum (juvenile hormone-producing gland) is controlled by the insulin receptor (InR); RNAi-InR reduces both InR and Hmgcr expression, and RNAi-Hmgcr blocks HMGCR, both disrupting sexual dimorphism of locomotor activity and producing dwarf flies, placing HMGCR downstream of InR in a pathway controlling body size and JH synthesis.","method":"Tissue-specific RNAi in corpus allatum using GAL4/UAS system, phenotypic analysis of locomotion and body size","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with tissue-specific RNAi, multiple phenotypic readouts","pmids":["17264888"],"is_preprint":false},{"year":2022,"finding":"The statin target Hmgcr in insulin-producing cells of the Drosophila pars intercerebralis (hypothalamic equivalent) regulates energy metabolism and feeding behavior: inhibiting central Hmgcr reduces insulin-like peptide expression, impairs insulin signaling, increases lipid storage, causes hyperglycemia, and induces hyperphagia dependent on the insulin-regulated α-glucosidase Tobi. In rats and mice, acute hypothalamic Hmgcr inhibition stimulates food intake.","method":"Drosophila tissue-specific RNAi, pharmacological inhibition, genetic epistasis with tobi, rat/mouse intrahypothalamic drug injection","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila with pharmacological validation in rodents","pmids":["35326421"],"is_preprint":false},{"year":2024,"finding":"Under glucose-oxygen deprivation in human monocytes, HMGCR function is constrained, reducing GGPP synthesis, which leads to decreased prenylation of Rac1, increased binding of non-prenylated Rac1 to IQGAP1, and NLRP3 inflammasome activation and IL-1β release.","method":"GGPP supplementation rescue, Rac1 prenylation assay, IQGAP1 co-immunoprecipitation, NLRP3 inflammasome activation assay, patient monocytes from mevalonate kinase deficiency and Muckle-Wells syndrome","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic pathway defined with biochemical assays, rescue experiments, and patient validation","pmids":["39012939"],"is_preprint":false},{"year":2023,"finding":"Bi-allelic loss-of-function missense variants in HMGCR cause autosomal-recessive limb-girdle muscular dystrophy; protein activity studies confirmed decreased enzymatic activity and reduced protein stability for variants p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln; molecular modeling showed variants are destabilizing and affect protein oligomerization.","method":"Whole exome sequencing, protein enzymatic activity assay, protein stability assay, molecular modeling, muscle biopsy histology","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — enzymatic activity confirmed in vitro for specific variants, supported by genetic and clinical evidence across five families","pmids":["37167966"],"is_preprint":false},{"year":2023,"finding":"A pathogenic homozygous loss-of-function missense mutation in HMGCR causes human limb-girdle muscular disease; mevalonolactone (mevalonate pathway product downstream of HMGCR) administered orally to patients rescues the disease phenotype and also resolves statin-induced myopathy in mice, demonstrating that HMGCR loss-of-function myopathy is caused by mevalonate pathway insufficiency.","method":"Homozygosity mapping, WES, functional analysis by confocal microscopy and biochemical/biophysical methods, mevalonolactone synthesis and oral administration in mice and human patient","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct genetic and pharmacological rescue in both human and mouse with biochemical validation","pmids":["36745799"],"is_preprint":false},{"year":2018,"finding":"HSP90 physically interacts with HMGCR (by co-immunoprecipitation) and stabilizes HMGCR protein by inhibiting its degradation in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, HSP90 inhibition, HMGCR protein stability assay, cell growth and migration assays","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP with partial mechanistic follow-up, single lab","pmids":["30483734"],"is_preprint":false},{"year":2017,"finding":"lncRNA ZFAS1 stabilizes HMGCR mRNA through U2AF2 (an RNA-binding protein): RNA pulldown and RIP assays demonstrate ZFAS1 binds U2AF2, which in turn binds HMGCR mRNA and increases its stability and expression in pancreatic carcinoma cells.","method":"RNA pulldown, RNA immunoprecipitation (RIP) assay, ZFAS1/U2AF2 knockdown, HMGCR mRNA stability assay","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct RNA interaction demonstrated by pulldown and RIP, single lab","pmids":["35846429"],"is_preprint":false},{"year":2021,"finding":"hnRNPR acts as a post-transcriptional repressor of HMGCR: it binds the 3'UTR of HMGCR mRNA (demonstrated by RNA immunoprecipitation and luciferase reporter assay) and reduces HMGCR mRNA stability and translation, thereby decreasing neuronal cholesterol levels.","method":"RNA immunoprecipitation, luciferase 3'UTR reporter assay, hnRNPR knockdown/overexpression in neuroblastoma cells, cholesterol measurement","journal":"Journal of integrative neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct RNA binding demonstrated with multiple assays, single lab","pmids":["34258925"],"is_preprint":false},{"year":2010,"finding":"Rational mutagenesis of the flap domain of human HMGCR (which has a role in statin binding) produces a catalytically active enzyme with ~38% decrease in K(app)M for substrate, ~2-fold increase in turnover number, and 480% increase in Ki for lovastatin, demonstrating that the flap domain is mechanistically important for statin inhibition.","method":"Site-directed mutagenesis, purified recombinant protein enzyme kinetics assay with wild-type and mutant HMGCR","journal":"Indian journal of biochemistry & biophysics","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstituted enzyme assay with defined mutagenesis, single lab","pmids":["21355415"],"is_preprint":false},{"year":2020,"finding":"HMGCR inhibition in renal cell carcinoma stabilizes the glycolytic enzyme PKM2 through increased HSP90 expression, promoting glycolysis and tumor growth; this effect is reversible by glycolysis inhibition with Shikonin (PKM2 inhibitor).","method":"HMGCR inhibition in RCC xenograft and cell models, HSP90/PKM2 protein level measurement, Seahorse glycolysis assay, pharmacological rescue","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo xenograft with mechanistic pathway rescue, single lab","pmids":["33905408"],"is_preprint":false},{"year":2020,"finding":"NPY stimulates hepatic cholesterol synthesis acutely via Y1 and Y5 receptors, activating the ERK1/2 signaling pathway to increase SREBP-2 processing and HMGCR protein expression, leading to cholesterol accumulation in hepatocytes.","method":"In vivo intraportal NPY injection in rats, BRL-3A hepatocyte culture with Y1/Y2/Y5 receptor antagonists and ERK1/2 antagonist, western blotting for HMGCR and SREBP-2","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological dissection of receptor and kinase pathway in vivo and in vitro, single lab","pmids":["32976883"],"is_preprint":false},{"year":2021,"finding":"AMPK downregulates HMGCR in regulatory T cells, which activates p38 MAPK that phosphorylates GSK-3β, reducing PD-1 expression; deletion of AMPKα1 in Tregs promotes HMGCR expression and increases PD-1.","method":"AMPKα1-conditional knockout in Tregs (Foxp3YFP-Cre mice), flow cytometry, western blotting, immunoprecipitation, immunofluorescence, tumor growth assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with mechanistic pathway biochemistry, single lab","pmids":["34649584"],"is_preprint":false},{"year":2020,"finding":"In BRAF-inhibitor resistant melanomas with suppressed PGC1α, statin (HMGCR inhibitor) vulnerability is mechanistically linked to reduced RAB6B and RAB27A prenylation, which impairs their membrane association and disrupts integrin-FAK signaling required for growth; re-expression of RAB6B and RAB27A reverses statin vulnerability.","method":"Pharmacological screen, siRNA knockdown and overexpression of RAB6B/RAB27A, prenylation assay, integrin-FAK signaling assay, cell viability assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway defined by rescue with specific prenylation targets, single lab","pmids":["37277330"],"is_preprint":false},{"year":2018,"finding":"Anti-HMGCR autoantibodies from IMNM patients bind HMGCR protein present on the sarcolemma of myofibers and activate the classical complement pathway (IgG deposition and complement cascade activation), leading to myofiber necrosis; the degree of sarcolemmal complement deposits correlates with fiber necrosis (r=0.4, p=0.004).","method":"In vitro immunostaining of primary muscle cells with purified patient-derived autoantibodies, reverse transcription PCR, immunostaining of muscle biopsies, complement deposition quantification","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct demonstration of autoantibody binding and complement activation on cells, correlated with pathology","pmids":["29330311"],"is_preprint":false},{"year":2022,"finding":"C5 complement inhibition (zilucoplan) prevents anti-HMGCR antibody-mediated necrotizing myopathy in a humanized mouse model, demonstrating that C5b-9 complement membrane attack complex deposition downstream of anti-HMGCR IgG is mechanistically required for myofiber injury.","method":"Co-injection of purified anti-HMGCR IgG with human complement into C57BL/6, C5-deficient B10, and Rag2-/- mice; zilucoplan treatment; muscle strength measurement, C5b-9 immunostaining, fiber regeneration quantification","journal":"Biomedicines","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic complement pathway demonstrated in multiple mouse models with pharmacological intervention","pmids":["36009583"],"is_preprint":false},{"year":2020,"finding":"Discovery of an orally active VHL-recruiting PROTAC (21c) that induces proteasomal degradation of HMGCR (DC50=120 nmol/L in Insig-silenced HepG2 cells) by forming a ternary complex with VHL E3 ligase and HMGCR, demonstrating that HMGCR can be degraded through VHL-mediated ubiquitin-proteasome pathway.","method":"PROTAC synthesis, HMGCR protein degradation assay, DC50 measurement, molecular modeling of ternary complex, in vivo cholesterol reduction in hypercholesterolemic mice","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct protein degradation assay with in vivo validation, single lab","pmids":["34094835"],"is_preprint":false},{"year":2008,"finding":"CREM isoforms regulate the circadian expression of HMGCR in mouse liver: in Crem-/- livers, HMGCR circadian phase is advanced (from CT20 to CT12), coinciding with phase advance of the lathosterol/cholesterol ratio, but HMGCR proximal promoter is not directly responsive to CREMtau/ICER overexpression.","method":"Crem knockout mice, circadian expression profiling, GC-MS sterol analysis, promoter luciferase assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with metabolic readout and promoter assay, single lab","pmids":["18775413"],"is_preprint":false},{"year":2012,"finding":"Maternal low-protein diet causes promoter hypomethylation and histone modification changes (decreased H3K9me1 and H3K27me3, increased H3 acetylation) at the HMGCR gene in offspring piglet livers, associated with increased HMGCR mRNA, protein expression, and enzyme activity.","method":"Bisulfite sequencing/MSP for DNA methylation, ChIP for histone modifications, HMGCR mRNA/protein measurement, enzymatic activity assay","journal":"The Journal of nutritional biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple epigenetic and functional assays in an animal model, single lab","pmids":["22444501"],"is_preprint":false},{"year":2015,"finding":"HMGCR is a direct target of hsa-miR-195 in breast cancer cells; ectopic miR-195 expression reduces HMGCR protein levels, decreasing cellular cholesterol and triglyceride levels and inhibiting proliferation, invasion, and migration.","method":"Luciferase reporter assay (3'UTR targeting), miR-195 overexpression, cholesterol/triglyceride measurement, functional assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'UTR reporter assay with functional readouts, single lab","pmids":["26632252"],"is_preprint":false},{"year":2015,"finding":"HMGCR is a direct target of miR-21 in hepatocytes: luciferase reporter assay confirmed miR-21 targets the HMGCR 3'UTR, and miR-21 reduces HMGCR mRNA and protein levels, decreasing triglycerides and cholesterol in a NAFLD cell model; HMGCR overexpression attenuates this effect.","method":"Luciferase 3'UTR reporter assay, miR-21 transfection in HepG2 cells, HMGCR overexpression rescue, lipid measurement","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct 3'UTR targeting confirmed with rescue experiment, single lab","pmids":["25605429"],"is_preprint":false},{"year":2017,"finding":"miR-29a/b/c suppress HMGCR expression by directly targeting HMGCR mRNA 3'UTR (validated by luciferase reporter), and miR-29a overexpression in hepatic cells reduces HMGCR protein and free cholesterol levels; Dicer1/miR-29 axis regulates hepatic free cholesterol accumulation.","method":"miRNA screening, luciferase 3'UTR reporter assay, miR-29a overexpression, HMGCR protein measurement, liver-specific Dicer1 knockout mice","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'UTR reporter assay plus in vivo Dicer1 KO model, single lab","pmids":["28112179"],"is_preprint":false},{"year":2015,"finding":"AMPK activation (by AICAR) directly inhibits SREBP-2 and its target gene HMGCR: AMPK phosphorylates threonine residues in both precursor and nuclear SREBP-2 forms, suppressing HMGCR expression and antagonizing TSH-stimulated HMGCR upregulation in hepatocytes.","method":"AICAR treatment of HepG2 cells and TSH receptor KO mice, AMPK kinase assay, SREBP-2 phosphorylation assay, HMGCR mRNA/protein measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — kinase assay combined with genetic model, single lab","pmids":["25933205"],"is_preprint":false},{"year":2024,"finding":"HMGCR promotes stemness and metastasis of hepatocellular carcinoma via activation of Hedgehog signaling: HMGCR positively correlates with Smoothened receptor expression and facilitates nuclear translocation of GLI1; Hedgehog pathway inhibition reverses HMGCR-driven stemness and metastasis.","method":"HMGCR overexpression/knockdown, Hedgehog pathway inhibitor screen, GLI1 nuclear translocation assay, in vitro stemness/metastasis assays and in vivo tumor models","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway placement by pharmacological inhibitor rescue with in vivo validation, single lab","pmids":["39022130"],"is_preprint":false}],"current_model":"HMGCR is the ER-resident, rate-limiting enzyme of the mevalonate/cholesterol biosynthesis pathway catalyzing HMG-CoA to mevalonate conversion; it is tightly regulated post-translationally through sterol-stimulated ubiquitylation (requiring E2 UBE2G2) and proteasomal degradation via the UBXD8-dependent ERAD machinery, stabilized in the fed state by mTORC1-phosphorylated USP20 deubiquitylase, transcriptionally controlled by SREBP-2 acting on dual SREs in its promoter, and subject to alternative splicing of exon 13 (modulated by HNRNPA1/rs3846662) that abolishes enzymatic activity; downstream, HMGCR-derived geranylgeranyl pyrophosphate is required for prenylation of Rho GTPases (including Rac1 and Cdc42) that regulate vascular stability and innate immune signaling, and its activity in central insulin-producing neurons influences feeding behavior and energy metabolism."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing HMGCR as a metabolic node downstream of insulin receptor signaling: tissue-specific RNAi in Drosophila corpus allatum showed that InR controls Hmgcr expression and that Hmgcr loss phenocopies InR loss for body size and sexual dimorphism of locomotion.","evidence":"GAL4/UAS-driven RNAi of InR and Hmgcr in Drosophila corpus allatum with phenotypic analysis","pmids":["17264888"],"confidence":"High","gaps":["Whether this InR→Hmgcr axis operates in mammalian endocrine tissues","Mechanism of InR-mediated transcriptional control of Hmgcr"]},{"year":2008,"claim":"Defining how genetic variation controls HMGCR isoform balance: the intronic SNP rs3846662 modulates exon 13 splicing, and the exon-13-skipped isoform is catalytically dead, establishing that alternative splicing is a physiologically relevant mode of HMGCR regulation.","evidence":"Minigene splicing assay, enzymatic complementation in HMGCR-deficient UT-2 cells, human lymphoblastoid cell lines","pmids":["18802019"],"confidence":"High","gaps":["Trans-acting factors mediating the splicing switch were unknown at this time","In vivo impact on plasma LDL-C was correlational"]},{"year":2010,"claim":"Characterizing the statin-binding flap domain: mutagenesis showed that the flap domain directly modulates substrate affinity and statin inhibition kinetics, revealing a structural basis for pharmacological targeting.","evidence":"Site-directed mutagenesis of purified recombinant HMGCR with steady-state enzyme kinetics","pmids":["21355415"],"confidence":"Medium","gaps":["No crystal structure of mutant enzyme was solved","In vivo relevance of flap domain variants not tested"]},{"year":2012,"claim":"Linking HMGCR to non-cholesterol outputs in vascular biology: HMGCR inhibition in zebrafish caused cerebral hemorrhage rescued specifically by GGPP, and GGTase-I depletion phenocopied HMGCR loss, establishing protein geranylgeranylation (including Cdc42 prenylation) as the critical downstream branch for vascular stability.","evidence":"Pharmacological inhibition, morpholino knockdown, GGPP rescue in zebrafish with live imaging","pmids":["23206891"],"confidence":"High","gaps":["Specific prenylated GTPase substrates beyond Cdc42 not individually tested","Translation to mammalian cerebrovascular biology not demonstrated"]},{"year":2013,"claim":"Identifying the trans-acting splicing factor for HMGCR exon 13: HNRNPA1 directly binds the rs3846662 region and promotes exon 13 skipping in an allele-dependent manner, reducing HMGCR activity and increasing LDL-C uptake.","evidence":"RNA-binding assay, HNRNPA1 overexpression, HMGCR enzyme activity and LDL uptake assays in hepatoma cells","pmids":["24001602"],"confidence":"High","gaps":["Whether other splicing factors cooperate with HNRNPA1 at this site","In vivo validation in liver tissue not performed"]},{"year":2015,"claim":"Expanding transcriptional and post-transcriptional control: AMPK phosphorylates SREBP-2 to suppress HMGCR transcription, an estrogen response element in the HMGCR promoter mediates E2-dependent upregulation, and miR-21 and miR-195 directly target the HMGCR 3′UTR to reduce expression.","evidence":"AMPK kinase assay and TSH receptor KO mice; ERE identification with in vivo ovarian stimulation; luciferase 3′UTR reporter assays for miRNAs","pmids":["25933205","25961186","26632252","25605429"],"confidence":"Medium","gaps":["Relative quantitative contribution of each miRNA in physiological contexts unknown","Estrogen-dependent regulation not validated in primary human hepatocytes"]},{"year":2017,"claim":"Resolving the ERAD machinery for sterol-induced HMGCR degradation: an unbiased haploid genetic screen identified UBXD8 as essential for extracting ubiquitylated HMGCR from the ER membrane for proteasomal degradation, and SREBP-2 was shown to activate HMGCR transcription via dual SREs requiring high SREBP-2 levels.","evidence":"Haploid CRISPR screen with endogenous HMGCR-mNeon tag; luciferase reporter, EMSA, and ChIP for SREBP-2/SRE characterization","pmids":["28882874","28342963"],"confidence":"High","gaps":["How UBXD8 cooperates with p97/VCP for HMGCR extraction not fully delineated","Threshold model of SREBP-2 levels not tested across nutritional states in vivo"]},{"year":2018,"claim":"Identifying the dedicated E2 enzyme and a pathogenic autoantibody mechanism: UBE2G2 was identified as the specific E2 ubiquitin-conjugating enzyme for sterol-stimulated HMGCR ubiquitylation, and anti-HMGCR autoantibodies from immune-mediated necrotizing myopathy patients were shown to bind sarcolemmal HMGCR and activate the classical complement pathway.","evidence":"CRISPR E2 screen with ubiquitylation assays; immunostaining of primary muscle cells with patient autoantibodies and complement deposition quantification","pmids":["30658189","29330311"],"confidence":"High","gaps":["E3 ligase partnering with UBE2G2 for HMGCR ubiquitylation not definitively identified in this study","Whether complement activation alone is sufficient for full IMNM pathology"]},{"year":2019,"claim":"Identifying the physiological sterol signal: lanosterol was established as the endogenous sterol intermediate that specifically triggers HMGCR degradation, while other C4-dimethylated intermediates regulate both HMGCR degradation and SREBP-2 cleavage.","evidence":"Systematic CRISPR deletion of mevalonate pathway enzymes combined with lipidomics in HeLa cells","pmids":["31455613"],"confidence":"High","gaps":["Whether lanosterol acts by direct binding to the HMGCR sterol-sensing domain or via Insig was not resolved","In vivo validation of individual sterol contributions not performed"]},{"year":2020,"claim":"Discovering the fed-state stabilization mechanism: mTORC1 phosphorylates USP20 at S132/S134 in response to insulin/glucose, recruiting USP20 to deubiquitylate and stabilize HMGCR, directly coupling nutritional state to cholesterol biosynthetic flux.","evidence":"Liver-specific Usp20 KO, USP20 phosphosite knock-in mice, co-IP, ubiquitylation assays, rescue with HMGCR(K248R)","pmids":["33177714"],"confidence":"High","gaps":["Whether USP20 also stabilizes other ER-resident mevalonate pathway enzymes","Quantitative contribution relative to transcriptional regulation in vivo"]},{"year":2022,"claim":"Extending HMGCR function to central metabolic control: Hmgcr in Drosophila insulin-producing neurons regulates insulin-like peptide expression, lipid storage, and feeding behavior via the α-glucosidase Tobi, and hypothalamic HMGCR inhibition in rodents stimulates food intake, establishing a conserved central role.","evidence":"Drosophila tissue-specific RNAi with genetic epistasis; rat/mouse intrahypothalamic drug injection","pmids":["35326421"],"confidence":"High","gaps":["Mammalian downstream mediators of hypothalamic HMGCR signaling not identified","Whether the effect is prenylation-dependent or cholesterol-dependent in neurons"]},{"year":2022,"claim":"Confirming complement as the effector in anti-HMGCR myopathy: C5 complement inhibition with zilucoplan prevented anti-HMGCR antibody-mediated myofiber injury in a humanized mouse model, validating C5b-9 membrane attack complex as the mechanistic effector.","evidence":"Purified anti-HMGCR IgG with human complement in multiple mouse models; zilucoplan pharmacological rescue","pmids":["36009583"],"confidence":"High","gaps":["Whether upstream complement components could also be targeted therapeutically","Long-term efficacy in human IMNM not tested"]},{"year":2023,"claim":"Establishing HMGCR as a Mendelian disease gene: bi-allelic loss-of-function missense variants cause autosomal-recessive limb-girdle muscular dystrophy, with decreased enzymatic activity and protein stability confirmed in vitro, and oral mevalonolactone rescues the disease phenotype in patients and statin myopathy in mice.","evidence":"WES across five families, enzymatic activity/stability assays, mevalonolactone oral administration rescue in human and mouse","pmids":["37167966","36745799"],"confidence":"High","gaps":["Tissue-specific mevalonate pathway insufficiency (muscle vs. other tissues) not fully characterized","Long-term outcomes of mevalonolactone supplementation unknown"]},{"year":2024,"claim":"Connecting HMGCR to innate immune inflammasome activation: under metabolic stress, reduced HMGCR-derived GGPP impairs Rac1 prenylation, causing non-prenylated Rac1 to bind IQGAP1 and activate the NLRP3 inflammasome, validated in patient monocytes from mevalonate kinase deficiency.","evidence":"GGPP rescue, Rac1 prenylation assay, IQGAP1 co-IP, NLRP3 activation assay in human monocytes including patient cells","pmids":["39012939"],"confidence":"High","gaps":["Whether other non-prenylated GTPases contribute to NLRP3 activation","Quantitative threshold of GGPP depletion required for inflammasome activation unknown"]},{"year":null,"claim":"Major unresolved questions include: the identity of the E3 ubiquitin ligase that partners with UBE2G2 for physiological sterol-induced HMGCR degradation, whether lanosterol directly engages the HMGCR sterol-sensing domain or acts via Insig, and the structural basis of HMGCR oligomerization changes caused by disease-associated variants.","evidence":"","pmids":[],"confidence":"Low","gaps":["E3 ligase identity for canonical sterol-induced degradation","Structural mechanism of lanosterol-sensing domain engagement","Full in vivo characterization of prenylation-dependent vs. cholesterol-dependent HMGCR functions across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[4,14,15,19]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,6,7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[24]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,4,5,8,10,11,13,14,15,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,24,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[21,32,33]}],"complexes":[],"partners":["USP20","UBXD8","UBE2G2","HNRNPA1","SREBF2","SIAH1","BRCC36","HSP90AA1"],"other_free_text":[]},"mechanistic_narrative":"HMGCR is the rate-limiting enzyme of the mevalonate pathway, catalyzing the conversion of HMG-CoA to mevalonate for cholesterol and isoprenoid biosynthesis, and its activity is subject to multilayered transcriptional, post-transcriptional, and post-translational regulation. Transcriptionally, HMGCR is controlled by SREBP-2 acting through dual sterol-regulatory elements in its promoter, with AMPK-mediated SREBP-2 phosphorylation suppressing expression [PMID:28342963, PMID:25933205]; post-transcriptionally, HNRNPA1-dependent alternative splicing of exon 13 (modulated by SNP rs3846662) produces a catalytically inactive isoform [PMID:18802019, PMID:24001602], and multiple miRNAs (miR-21, miR-29, miR-195) target the HMGCR 3′UTR to reduce mRNA stability [PMID:25605429, PMID:28112179]. Post-translationally, lanosterol-stimulated ubiquitylation by UBE2G2 and UBXD8-dependent ERAD drives proteasomal degradation, counterbalanced by mTORC1-phosphorylated USP20 deubiquitylase that stabilizes HMGCR in the fed state [PMID:31455613, PMID:28882874, PMID:30658189, PMID:33177714]. Downstream, HMGCR-derived geranylgeranyl pyrophosphate is essential for prenylation of Rho/Rab GTPases governing vascular stability, innate immune inflammasome activation, and integrin signaling, and bi-allelic loss-of-function HMGCR variants cause autosomal-recessive limb-girdle muscular dystrophy rescuable by oral mevalonolactone [PMID:23206891, PMID:39012939, PMID:37167966, PMID:36745799]."},"prefetch_data":{"uniprot":{"accession":"P04035","full_name":"3-hydroxy-3-methylglutaryl-coenzyme A reductase","aliases":[],"length_aa":888,"mass_kda":97.5,"function":"Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis (PubMed:21357570, PubMed:2991281, PubMed:36745799, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668, PubMed:36745799)","subcellular_location":"Endoplasmic reticulum membrane; Peroxisome membrane","url":"https://www.uniprot.org/uniprotkb/P04035/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HMGCR","classification":"Common Essential","n_dependent_lines":1041,"n_total_lines":1208,"dependency_fraction":0.8617549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HMGCR","total_profiled":1310},"omim":[{"mim_id":"620801","title":"GLYCEROL KINASE 5; GK5","url":"https://www.omim.org/entry/620801"},{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"},{"mim_id":"620410","title":"LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 3; LDLCQ3","url":"https://www.omim.org/entry/620410"},{"mim_id":"620379","title":"SPASTIC PARAPLEGIA 89, AUTOSOMAL RECESSIVE; SPG89","url":"https://www.omim.org/entry/620379"},{"mim_id":"620375","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 28; LGMDR28","url":"https://www.omim.org/entry/620375"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":98.8}],"url":"https://www.proteinatlas.org/search/HMGCR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P04035","domains":[{"cath_id":"1.20.1640","chopping":"1-37_58-225_236-263","consensus_level":"medium","plddt":76.8353,"start":1,"end":263},{"cath_id":"1.10.3270.10","chopping":"444-520","consensus_level":"high","plddt":90.9223,"start":444,"end":520},{"cath_id":"3.90.770.10","chopping":"537-585_693-869","consensus_level":"high","plddt":95.8879,"start":537,"end":869},{"cath_id":"3.30.70.420","chopping":"592-681","consensus_level":"high","plddt":97.127,"start":592,"end":681}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04035","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04035-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04035-F1-predicted_aligned_error_v6.png","plddt_mean":75.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HMGCR","jax_strain_url":"https://www.jax.org/strain/search?query=HMGCR"},"sequence":{"accession":"P04035","fasta_url":"https://rest.uniprot.org/uniprotkb/P04035.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04035/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04035"}},"corpus_meta":[{"pmid":"25770315","id":"PMC_25770315","title":"Effect 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phosphorylates USP20 at S132 and S134 in response to postprandial insulin/glucose, which recruits USP20 to the HMGCR complex and antagonizes HMGCR ubiquitin-dependent degradation, thereby increasing cholesterol biosynthesis.\",\n      \"method\": \"Liver-specific Usp20 knockout mice, USP20(S132A/S134A) knock-in mice, co-immunoprecipitation, in vivo and in vitro ubiquitylation assays, rescue with constitutively stable HMGCR(K248R)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal genetic and biochemical methods in vivo and in vitro, causal rescue experiment\",\n      \"pmids\": [\"33177714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lanosterol is the bona fide endogenous sterol intermediate that specifically stimulates HMGCR degradation; other C4-dimethylated sterol intermediates (24,25-dihydrolanosterol, FFMAS, TMAS, dihydro-TMAS) regulate both HMGCR degradation and SREBP-2 cleavage inhibition, as demonstrated by CRISPR/Cas9 deletion of individual mevalonate pathway enzymes and lipidomics.\",\n      \"method\": \"CRISPR/Cas9 gene deletion of mevalonate pathway enzymes, lipidomics, immunoblot for HMGCR and SREBP-2 status in HeLa cells expressing mevalonate transporter\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic CRISPR knockouts combined with lipidomics and functional readouts in a single rigorous study\",\n      \"pmids\": [\"31455613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBXD8 is an essential mediator of sterol-stimulated proteasomal degradation of HMGCR: it is required for dislocation of ubiquitylated HMGCR from the ER membrane en route to proteasomal degradation, a function dependent on its UBX domain.\",\n      \"method\": \"Haploid mammalian genetic screen with CRISPR/Cas9-tagged endogenous HMGCR-mNeon, UBXD8 ablation in multiple cell types, domain mutagenesis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased genetic screen confirmed by mechanistic domain studies in multiple cell types\",\n      \"pmids\": [\"28882874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UBE2G2 is the E2 ubiquitin-conjugating enzyme specifically required for sterol-stimulated ubiquitylation and degradation of HMGCR (distinct from SQLE which uses UBE2J2), identified by CRISPR/Cas9 screen of ERAD-associated E2 enzymes.\",\n      \"method\": \"CRISPR/Cas9-based E2 enzyme screen, ubiquitylation assays, HMGCR protein stability measurements in multiple human cell types\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic CRISPR screen with enzymatic activity validation across multiple cell types\",\n      \"pmids\": [\"30658189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"An intronic SNP (rs3846662) in HMGCR modulates alternative splicing of exon 13; the minor allele is associated with up to 2.2-fold lower expression of the exon-13-skipped isoform, and the alternative splice variant lacking exon 13 cannot restore HMGCR enzymatic activity in HMGCR-deficient UT-2 cells.\",\n      \"method\": \"Minigene transfection splicing assay, in vitro complementation assay in HMGCR-deficient UT-2 cells, human lymphoblastoid cell lines\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional splicing assay plus enzymatic complementation assay, replicated across populations\",\n      \"pmids\": [\"18802019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HNRNPA1 directly binds the rs3846662 SNP site in HMGCR pre-mRNA and promotes exon 13 skipping in an allele-dependent manner; HNRNPA1 overexpression also specifically stabilizes the exon-13-skipped HMGCR transcript, reduces HMGCR enzyme activity, enhances LDL-C uptake, and increases cellular apoB.\",\n      \"method\": \"HNRNPA1 RNA-binding assay, HNRNPA1 overexpression, HMGCR enzyme activity assay, LDL uptake assay, hepatoma cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated, multiple functional readouts, consistent with two independent clinical trial datasets\",\n      \"pmids\": [\"24001602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRCC36 deubiquitinates HMGCR in a DUB activity-dependent manner; HMGCR localization shifts from mitochondria during ferroptosis to the endoplasmic reticulum during pyroptosis, and BRCC36-mediated HMGCR stabilization inhibits ferroptosis while promoting pyroptosis.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitylation assay, immunofluorescence subcellular localization, BRCC36 inhibitor (thiolutin), cell death assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus pharmacological inhibitor, single lab\",\n      \"pmids\": [\"38178583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIAH1, an E3 ubiquitin ligase, ubiquitinates HMGCR, thereby modulating cholesterol synthesis and efflux protein activity in lung cancer cells; SIAH1 overexpression suppresses tumor growth and enhances cisplatin sensitivity in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, HMGCR knockdown and SIAH1 overexpression in vitro and xenograft models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — biochemical ubiquitylation assay supported by in vivo xenograft, single lab\",\n      \"pmids\": [\"37062828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SREBP-2 activates human HMGCR transcription via two sterol-regulatory elements (SREs) and one NF-Y site in the HMGCR promoter; HMGCR expression is highly activated only when SREBP-2 levels are very high, unlike LDLR which responds at lower SREBP-2 levels.\",\n      \"method\": \"Luciferase reporter assays with SRE/NF-Y mutant library, electrophoretic mobility shift assay (EMSA), ChIP-PCR\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (reporter assay, EMSA, ChIP) in one study\",\n      \"pmids\": [\"28342963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"An estrogen response element (ERE) in the HMGCR promoter mediates estradiol-dependent upregulation of HMGCR expression in hepatocytes, leading to increased cholesterol synthesis.\",\n      \"method\": \"Promoter ERE identification, E2 treatment of HepG2 cells and mouse fetal hepatocytes, in vivo ovarian stimulation mouse model with HMGCR expression measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ERE identified with in vitro and in vivo concordance, single lab\",\n      \"pmids\": [\"25961186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HMGCR pathway activity in zebrafish is required for developmental cerebral vascular stability through protein geranylgeranylation: HMGCR inhibition causes cerebral hemorrhage rescued by geranylgeranyl pyrophosphate (GGPP) supplementation; depletion of GGTase-I (β-subunit) mimics HMGCR loss-of-function and reduces endothelial Cdc42 expression.\",\n      \"method\": \"Pharmacological HMGCR inhibition, genetic morpholino knockdown of GGTase-I β-subunit, GGPP rescue in zebrafish, live imaging\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — pharmacological and genetic approaches with specific pathway rescue in vivo\",\n      \"pmids\": [\"23206891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, Hmgcr expression in the corpus allatum (juvenile hormone-producing gland) is controlled by the insulin receptor (InR); RNAi-InR reduces both InR and Hmgcr expression, and RNAi-Hmgcr blocks HMGCR, both disrupting sexual dimorphism of locomotor activity and producing dwarf flies, placing HMGCR downstream of InR in a pathway controlling body size and JH synthesis.\",\n      \"method\": \"Tissue-specific RNAi in corpus allatum using GAL4/UAS system, phenotypic analysis of locomotion and body size\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with tissue-specific RNAi, multiple phenotypic readouts\",\n      \"pmids\": [\"17264888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The statin target Hmgcr in insulin-producing cells of the Drosophila pars intercerebralis (hypothalamic equivalent) regulates energy metabolism and feeding behavior: inhibiting central Hmgcr reduces insulin-like peptide expression, impairs insulin signaling, increases lipid storage, causes hyperglycemia, and induces hyperphagia dependent on the insulin-regulated α-glucosidase Tobi. In rats and mice, acute hypothalamic Hmgcr inhibition stimulates food intake.\",\n      \"method\": \"Drosophila tissue-specific RNAi, pharmacological inhibition, genetic epistasis with tobi, rat/mouse intrahypothalamic drug injection\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila with pharmacological validation in rodents\",\n      \"pmids\": [\"35326421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under glucose-oxygen deprivation in human monocytes, HMGCR function is constrained, reducing GGPP synthesis, which leads to decreased prenylation of Rac1, increased binding of non-prenylated Rac1 to IQGAP1, and NLRP3 inflammasome activation and IL-1β release.\",\n      \"method\": \"GGPP supplementation rescue, Rac1 prenylation assay, IQGAP1 co-immunoprecipitation, NLRP3 inflammasome activation assay, patient monocytes from mevalonate kinase deficiency and Muckle-Wells syndrome\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic pathway defined with biochemical assays, rescue experiments, and patient validation\",\n      \"pmids\": [\"39012939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bi-allelic loss-of-function missense variants in HMGCR cause autosomal-recessive limb-girdle muscular dystrophy; protein activity studies confirmed decreased enzymatic activity and reduced protein stability for variants p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln; molecular modeling showed variants are destabilizing and affect protein oligomerization.\",\n      \"method\": \"Whole exome sequencing, protein enzymatic activity assay, protein stability assay, molecular modeling, muscle biopsy histology\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic activity confirmed in vitro for specific variants, supported by genetic and clinical evidence across five families\",\n      \"pmids\": [\"37167966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A pathogenic homozygous loss-of-function missense mutation in HMGCR causes human limb-girdle muscular disease; mevalonolactone (mevalonate pathway product downstream of HMGCR) administered orally to patients rescues the disease phenotype and also resolves statin-induced myopathy in mice, demonstrating that HMGCR loss-of-function myopathy is caused by mevalonate pathway insufficiency.\",\n      \"method\": \"Homozygosity mapping, WES, functional analysis by confocal microscopy and biochemical/biophysical methods, mevalonolactone synthesis and oral administration in mice and human patient\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct genetic and pharmacological rescue in both human and mouse with biochemical validation\",\n      \"pmids\": [\"36745799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HSP90 physically interacts with HMGCR (by co-immunoprecipitation) and stabilizes HMGCR protein by inhibiting its degradation in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, HSP90 inhibition, HMGCR protein stability assay, cell growth and migration assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with partial mechanistic follow-up, single lab\",\n      \"pmids\": [\"30483734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"lncRNA ZFAS1 stabilizes HMGCR mRNA through U2AF2 (an RNA-binding protein): RNA pulldown and RIP assays demonstrate ZFAS1 binds U2AF2, which in turn binds HMGCR mRNA and increases its stability and expression in pancreatic carcinoma cells.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation (RIP) assay, ZFAS1/U2AF2 knockdown, HMGCR mRNA stability assay\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct RNA interaction demonstrated by pulldown and RIP, single lab\",\n      \"pmids\": [\"35846429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPR acts as a post-transcriptional repressor of HMGCR: it binds the 3'UTR of HMGCR mRNA (demonstrated by RNA immunoprecipitation and luciferase reporter assay) and reduces HMGCR mRNA stability and translation, thereby decreasing neuronal cholesterol levels.\",\n      \"method\": \"RNA immunoprecipitation, luciferase 3'UTR reporter assay, hnRNPR knockdown/overexpression in neuroblastoma cells, cholesterol measurement\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct RNA binding demonstrated with multiple assays, single lab\",\n      \"pmids\": [\"34258925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rational mutagenesis of the flap domain of human HMGCR (which has a role in statin binding) produces a catalytically active enzyme with ~38% decrease in K(app)M for substrate, ~2-fold increase in turnover number, and 480% increase in Ki for lovastatin, demonstrating that the flap domain is mechanistically important for statin inhibition.\",\n      \"method\": \"Site-directed mutagenesis, purified recombinant protein enzyme kinetics assay with wild-type and mutant HMGCR\",\n      \"journal\": \"Indian journal of biochemistry & biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted enzyme assay with defined mutagenesis, single lab\",\n      \"pmids\": [\"21355415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HMGCR inhibition in renal cell carcinoma stabilizes the glycolytic enzyme PKM2 through increased HSP90 expression, promoting glycolysis and tumor growth; this effect is reversible by glycolysis inhibition with Shikonin (PKM2 inhibitor).\",\n      \"method\": \"HMGCR inhibition in RCC xenograft and cell models, HSP90/PKM2 protein level measurement, Seahorse glycolysis assay, pharmacological rescue\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo xenograft with mechanistic pathway rescue, single lab\",\n      \"pmids\": [\"33905408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NPY stimulates hepatic cholesterol synthesis acutely via Y1 and Y5 receptors, activating the ERK1/2 signaling pathway to increase SREBP-2 processing and HMGCR protein expression, leading to cholesterol accumulation in hepatocytes.\",\n      \"method\": \"In vivo intraportal NPY injection in rats, BRL-3A hepatocyte culture with Y1/Y2/Y5 receptor antagonists and ERK1/2 antagonist, western blotting for HMGCR and SREBP-2\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of receptor and kinase pathway in vivo and in vitro, single lab\",\n      \"pmids\": [\"32976883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMPK downregulates HMGCR in regulatory T cells, which activates p38 MAPK that phosphorylates GSK-3β, reducing PD-1 expression; deletion of AMPKα1 in Tregs promotes HMGCR expression and increases PD-1.\",\n      \"method\": \"AMPKα1-conditional knockout in Tregs (Foxp3YFP-Cre mice), flow cytometry, western blotting, immunoprecipitation, immunofluorescence, tumor growth assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with mechanistic pathway biochemistry, single lab\",\n      \"pmids\": [\"34649584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In BRAF-inhibitor resistant melanomas with suppressed PGC1α, statin (HMGCR inhibitor) vulnerability is mechanistically linked to reduced RAB6B and RAB27A prenylation, which impairs their membrane association and disrupts integrin-FAK signaling required for growth; re-expression of RAB6B and RAB27A reverses statin vulnerability.\",\n      \"method\": \"Pharmacological screen, siRNA knockdown and overexpression of RAB6B/RAB27A, prenylation assay, integrin-FAK signaling assay, cell viability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined by rescue with specific prenylation targets, single lab\",\n      \"pmids\": [\"37277330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Anti-HMGCR autoantibodies from IMNM patients bind HMGCR protein present on the sarcolemma of myofibers and activate the classical complement pathway (IgG deposition and complement cascade activation), leading to myofiber necrosis; the degree of sarcolemmal complement deposits correlates with fiber necrosis (r=0.4, p=0.004).\",\n      \"method\": \"In vitro immunostaining of primary muscle cells with purified patient-derived autoantibodies, reverse transcription PCR, immunostaining of muscle biopsies, complement deposition quantification\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct demonstration of autoantibody binding and complement activation on cells, correlated with pathology\",\n      \"pmids\": [\"29330311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C5 complement inhibition (zilucoplan) prevents anti-HMGCR antibody-mediated necrotizing myopathy in a humanized mouse model, demonstrating that C5b-9 complement membrane attack complex deposition downstream of anti-HMGCR IgG is mechanistically required for myofiber injury.\",\n      \"method\": \"Co-injection of purified anti-HMGCR IgG with human complement into C57BL/6, C5-deficient B10, and Rag2-/- mice; zilucoplan treatment; muscle strength measurement, C5b-9 immunostaining, fiber regeneration quantification\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic complement pathway demonstrated in multiple mouse models with pharmacological intervention\",\n      \"pmids\": [\"36009583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Discovery of an orally active VHL-recruiting PROTAC (21c) that induces proteasomal degradation of HMGCR (DC50=120 nmol/L in Insig-silenced HepG2 cells) by forming a ternary complex with VHL E3 ligase and HMGCR, demonstrating that HMGCR can be degraded through VHL-mediated ubiquitin-proteasome pathway.\",\n      \"method\": \"PROTAC synthesis, HMGCR protein degradation assay, DC50 measurement, molecular modeling of ternary complex, in vivo cholesterol reduction in hypercholesterolemic mice\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein degradation assay with in vivo validation, single lab\",\n      \"pmids\": [\"34094835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CREM isoforms regulate the circadian expression of HMGCR in mouse liver: in Crem-/- livers, HMGCR circadian phase is advanced (from CT20 to CT12), coinciding with phase advance of the lathosterol/cholesterol ratio, but HMGCR proximal promoter is not directly responsive to CREMtau/ICER overexpression.\",\n      \"method\": \"Crem knockout mice, circadian expression profiling, GC-MS sterol analysis, promoter luciferase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with metabolic readout and promoter assay, single lab\",\n      \"pmids\": [\"18775413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Maternal low-protein diet causes promoter hypomethylation and histone modification changes (decreased H3K9me1 and H3K27me3, increased H3 acetylation) at the HMGCR gene in offspring piglet livers, associated with increased HMGCR mRNA, protein expression, and enzyme activity.\",\n      \"method\": \"Bisulfite sequencing/MSP for DNA methylation, ChIP for histone modifications, HMGCR mRNA/protein measurement, enzymatic activity assay\",\n      \"journal\": \"The Journal of nutritional biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple epigenetic and functional assays in an animal model, single lab\",\n      \"pmids\": [\"22444501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HMGCR is a direct target of hsa-miR-195 in breast cancer cells; ectopic miR-195 expression reduces HMGCR protein levels, decreasing cellular cholesterol and triglyceride levels and inhibiting proliferation, invasion, and migration.\",\n      \"method\": \"Luciferase reporter assay (3'UTR targeting), miR-195 overexpression, cholesterol/triglyceride measurement, functional assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR reporter assay with functional readouts, single lab\",\n      \"pmids\": [\"26632252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HMGCR is a direct target of miR-21 in hepatocytes: luciferase reporter assay confirmed miR-21 targets the HMGCR 3'UTR, and miR-21 reduces HMGCR mRNA and protein levels, decreasing triglycerides and cholesterol in a NAFLD cell model; HMGCR overexpression attenuates this effect.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, miR-21 transfection in HepG2 cells, HMGCR overexpression rescue, lipid measurement\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct 3'UTR targeting confirmed with rescue experiment, single lab\",\n      \"pmids\": [\"25605429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-29a/b/c suppress HMGCR expression by directly targeting HMGCR mRNA 3'UTR (validated by luciferase reporter), and miR-29a overexpression in hepatic cells reduces HMGCR protein and free cholesterol levels; Dicer1/miR-29 axis regulates hepatic free cholesterol accumulation.\",\n      \"method\": \"miRNA screening, luciferase 3'UTR reporter assay, miR-29a overexpression, HMGCR protein measurement, liver-specific Dicer1 knockout mice\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR reporter assay plus in vivo Dicer1 KO model, single lab\",\n      \"pmids\": [\"28112179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AMPK activation (by AICAR) directly inhibits SREBP-2 and its target gene HMGCR: AMPK phosphorylates threonine residues in both precursor and nuclear SREBP-2 forms, suppressing HMGCR expression and antagonizing TSH-stimulated HMGCR upregulation in hepatocytes.\",\n      \"method\": \"AICAR treatment of HepG2 cells and TSH receptor KO mice, AMPK kinase assay, SREBP-2 phosphorylation assay, HMGCR mRNA/protein measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinase assay combined with genetic model, single lab\",\n      \"pmids\": [\"25933205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMGCR promotes stemness and metastasis of hepatocellular carcinoma via activation of Hedgehog signaling: HMGCR positively correlates with Smoothened receptor expression and facilitates nuclear translocation of GLI1; Hedgehog pathway inhibition reverses HMGCR-driven stemness and metastasis.\",\n      \"method\": \"HMGCR overexpression/knockdown, Hedgehog pathway inhibitor screen, GLI1 nuclear translocation assay, in vitro stemness/metastasis assays and in vivo tumor models\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement by pharmacological inhibitor rescue with in vivo validation, single lab\",\n      \"pmids\": [\"39022130\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMGCR is the ER-resident, rate-limiting enzyme of the mevalonate/cholesterol biosynthesis pathway catalyzing HMG-CoA to mevalonate conversion; it is tightly regulated post-translationally through sterol-stimulated ubiquitylation (requiring E2 UBE2G2) and proteasomal degradation via the UBXD8-dependent ERAD machinery, stabilized in the fed state by mTORC1-phosphorylated USP20 deubiquitylase, transcriptionally controlled by SREBP-2 acting on dual SREs in its promoter, and subject to alternative splicing of exon 13 (modulated by HNRNPA1/rs3846662) that abolishes enzymatic activity; downstream, HMGCR-derived geranylgeranyl pyrophosphate is required for prenylation of Rho GTPases (including Rac1 and Cdc42) that regulate vascular stability and innate immune signaling, and its activity in central insulin-producing neurons influences feeding behavior and energy metabolism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HMGCR is the rate-limiting enzyme of the mevalonate pathway, catalyzing the conversion of HMG-CoA to mevalonate for cholesterol and isoprenoid biosynthesis, and its activity is subject to multilayered transcriptional, post-transcriptional, and post-translational regulation. Transcriptionally, HMGCR is controlled by SREBP-2 acting through dual sterol-regulatory elements in its promoter, with AMPK-mediated SREBP-2 phosphorylation suppressing expression [PMID:28342963, PMID:25933205]; post-transcriptionally, HNRNPA1-dependent alternative splicing of exon 13 (modulated by SNP rs3846662) produces a catalytically inactive isoform [PMID:18802019, PMID:24001602], and multiple miRNAs (miR-21, miR-29, miR-195) target the HMGCR 3′UTR to reduce mRNA stability [PMID:25605429, PMID:28112179]. Post-translationally, lanosterol-stimulated ubiquitylation by UBE2G2 and UBXD8-dependent ERAD drives proteasomal degradation, counterbalanced by mTORC1-phosphorylated USP20 deubiquitylase that stabilizes HMGCR in the fed state [PMID:31455613, PMID:28882874, PMID:30658189, PMID:33177714]. Downstream, HMGCR-derived geranylgeranyl pyrophosphate is essential for prenylation of Rho/Rab GTPases governing vascular stability, innate immune inflammasome activation, and integrin signaling, and bi-allelic loss-of-function HMGCR variants cause autosomal-recessive limb-girdle muscular dystrophy rescuable by oral mevalonolactone [PMID:23206891, PMID:39012939, PMID:37167966, PMID:36745799].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing HMGCR as a metabolic node downstream of insulin receptor signaling: tissue-specific RNAi in Drosophila corpus allatum showed that InR controls Hmgcr expression and that Hmgcr loss phenocopies InR loss for body size and sexual dimorphism of locomotion.\",\n      \"evidence\": \"GAL4/UAS-driven RNAi of InR and Hmgcr in Drosophila corpus allatum with phenotypic analysis\",\n      \"pmids\": [\"17264888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this InR→Hmgcr axis operates in mammalian endocrine tissues\", \"Mechanism of InR-mediated transcriptional control of Hmgcr\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining how genetic variation controls HMGCR isoform balance: the intronic SNP rs3846662 modulates exon 13 splicing, and the exon-13-skipped isoform is catalytically dead, establishing that alternative splicing is a physiologically relevant mode of HMGCR regulation.\",\n      \"evidence\": \"Minigene splicing assay, enzymatic complementation in HMGCR-deficient UT-2 cells, human lymphoblastoid cell lines\",\n      \"pmids\": [\"18802019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting factors mediating the splicing switch were unknown at this time\", \"In vivo impact on plasma LDL-C was correlational\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Characterizing the statin-binding flap domain: mutagenesis showed that the flap domain directly modulates substrate affinity and statin inhibition kinetics, revealing a structural basis for pharmacological targeting.\",\n      \"evidence\": \"Site-directed mutagenesis of purified recombinant HMGCR with steady-state enzyme kinetics\",\n      \"pmids\": [\"21355415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of mutant enzyme was solved\", \"In vivo relevance of flap domain variants not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking HMGCR to non-cholesterol outputs in vascular biology: HMGCR inhibition in zebrafish caused cerebral hemorrhage rescued specifically by GGPP, and GGTase-I depletion phenocopied HMGCR loss, establishing protein geranylgeranylation (including Cdc42 prenylation) as the critical downstream branch for vascular stability.\",\n      \"evidence\": \"Pharmacological inhibition, morpholino knockdown, GGPP rescue in zebrafish with live imaging\",\n      \"pmids\": [\"23206891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific prenylated GTPase substrates beyond Cdc42 not individually tested\", \"Translation to mammalian cerebrovascular biology not demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying the trans-acting splicing factor for HMGCR exon 13: HNRNPA1 directly binds the rs3846662 region and promotes exon 13 skipping in an allele-dependent manner, reducing HMGCR activity and increasing LDL-C uptake.\",\n      \"evidence\": \"RNA-binding assay, HNRNPA1 overexpression, HMGCR enzyme activity and LDL uptake assays in hepatoma cells\",\n      \"pmids\": [\"24001602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other splicing factors cooperate with HNRNPA1 at this site\", \"In vivo validation in liver tissue not performed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanding transcriptional and post-transcriptional control: AMPK phosphorylates SREBP-2 to suppress HMGCR transcription, an estrogen response element in the HMGCR promoter mediates E2-dependent upregulation, and miR-21 and miR-195 directly target the HMGCR 3′UTR to reduce expression.\",\n      \"evidence\": \"AMPK kinase assay and TSH receptor KO mice; ERE identification with in vivo ovarian stimulation; luciferase 3′UTR reporter assays for miRNAs\",\n      \"pmids\": [\"25933205\", \"25961186\", \"26632252\", \"25605429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative quantitative contribution of each miRNA in physiological contexts unknown\", \"Estrogen-dependent regulation not validated in primary human hepatocytes\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolving the ERAD machinery for sterol-induced HMGCR degradation: an unbiased haploid genetic screen identified UBXD8 as essential for extracting ubiquitylated HMGCR from the ER membrane for proteasomal degradation, and SREBP-2 was shown to activate HMGCR transcription via dual SREs requiring high SREBP-2 levels.\",\n      \"evidence\": \"Haploid CRISPR screen with endogenous HMGCR-mNeon tag; luciferase reporter, EMSA, and ChIP for SREBP-2/SRE characterization\",\n      \"pmids\": [\"28882874\", \"28342963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How UBXD8 cooperates with p97/VCP for HMGCR extraction not fully delineated\", \"Threshold model of SREBP-2 levels not tested across nutritional states in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying the dedicated E2 enzyme and a pathogenic autoantibody mechanism: UBE2G2 was identified as the specific E2 ubiquitin-conjugating enzyme for sterol-stimulated HMGCR ubiquitylation, and anti-HMGCR autoantibodies from immune-mediated necrotizing myopathy patients were shown to bind sarcolemmal HMGCR and activate the classical complement pathway.\",\n      \"evidence\": \"CRISPR E2 screen with ubiquitylation assays; immunostaining of primary muscle cells with patient autoantibodies and complement deposition quantification\",\n      \"pmids\": [\"30658189\", \"29330311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase partnering with UBE2G2 for HMGCR ubiquitylation not definitively identified in this study\", \"Whether complement activation alone is sufficient for full IMNM pathology\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying the physiological sterol signal: lanosterol was established as the endogenous sterol intermediate that specifically triggers HMGCR degradation, while other C4-dimethylated intermediates regulate both HMGCR degradation and SREBP-2 cleavage.\",\n      \"evidence\": \"Systematic CRISPR deletion of mevalonate pathway enzymes combined with lipidomics in HeLa cells\",\n      \"pmids\": [\"31455613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lanosterol acts by direct binding to the HMGCR sterol-sensing domain or via Insig was not resolved\", \"In vivo validation of individual sterol contributions not performed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovering the fed-state stabilization mechanism: mTORC1 phosphorylates USP20 at S132/S134 in response to insulin/glucose, recruiting USP20 to deubiquitylate and stabilize HMGCR, directly coupling nutritional state to cholesterol biosynthetic flux.\",\n      \"evidence\": \"Liver-specific Usp20 KO, USP20 phosphosite knock-in mice, co-IP, ubiquitylation assays, rescue with HMGCR(K248R)\",\n      \"pmids\": [\"33177714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP20 also stabilizes other ER-resident mevalonate pathway enzymes\", \"Quantitative contribution relative to transcriptional regulation in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending HMGCR function to central metabolic control: Hmgcr in Drosophila insulin-producing neurons regulates insulin-like peptide expression, lipid storage, and feeding behavior via the α-glucosidase Tobi, and hypothalamic HMGCR inhibition in rodents stimulates food intake, establishing a conserved central role.\",\n      \"evidence\": \"Drosophila tissue-specific RNAi with genetic epistasis; rat/mouse intrahypothalamic drug injection\",\n      \"pmids\": [\"35326421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian downstream mediators of hypothalamic HMGCR signaling not identified\", \"Whether the effect is prenylation-dependent or cholesterol-dependent in neurons\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirming complement as the effector in anti-HMGCR myopathy: C5 complement inhibition with zilucoplan prevented anti-HMGCR antibody-mediated myofiber injury in a humanized mouse model, validating C5b-9 membrane attack complex as the mechanistic effector.\",\n      \"evidence\": \"Purified anti-HMGCR IgG with human complement in multiple mouse models; zilucoplan pharmacological rescue\",\n      \"pmids\": [\"36009583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether upstream complement components could also be targeted therapeutically\", \"Long-term efficacy in human IMNM not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing HMGCR as a Mendelian disease gene: bi-allelic loss-of-function missense variants cause autosomal-recessive limb-girdle muscular dystrophy, with decreased enzymatic activity and protein stability confirmed in vitro, and oral mevalonolactone rescues the disease phenotype in patients and statin myopathy in mice.\",\n      \"evidence\": \"WES across five families, enzymatic activity/stability assays, mevalonolactone oral administration rescue in human and mouse\",\n      \"pmids\": [\"37167966\", \"36745799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific mevalonate pathway insufficiency (muscle vs. other tissues) not fully characterized\", \"Long-term outcomes of mevalonolactone supplementation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connecting HMGCR to innate immune inflammasome activation: under metabolic stress, reduced HMGCR-derived GGPP impairs Rac1 prenylation, causing non-prenylated Rac1 to bind IQGAP1 and activate the NLRP3 inflammasome, validated in patient monocytes from mevalonate kinase deficiency.\",\n      \"evidence\": \"GGPP rescue, Rac1 prenylation assay, IQGAP1 co-IP, NLRP3 activation assay in human monocytes including patient cells\",\n      \"pmids\": [\"39012939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other non-prenylated GTPases contribute to NLRP3 activation\", \"Quantitative threshold of GGPP depletion required for inflammasome activation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: the identity of the E3 ubiquitin ligase that partners with UBE2G2 for physiological sterol-induced HMGCR degradation, whether lanosterol directly engages the HMGCR sterol-sensing domain or acts via Insig, and the structural basis of HMGCR oligomerization changes caused by disease-associated variants.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"E3 ligase identity for canonical sterol-induced degradation\", \"Structural mechanism of lanosterol-sensing domain engagement\", \"Full in vivo characterization of prenylation-dependent vs. cholesterol-dependent HMGCR functions across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [4, 14, 15, 19]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 4, 5, 8, 10, 11, 13, 14, 15, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 24, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [21, 32, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"USP20\",\n      \"UBXD8\",\n      \"UBE2G2\",\n      \"HNRNPA1\",\n      \"SREBF2\",\n      \"SIAH1\",\n      \"BRCC36\",\n      \"HSP90AA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}