{"gene":"HMGCR","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2020,"finding":"The deubiquitylase USP20 stabilizes HMGCR in the fed state by antagonizing its ubiquitin-dependent degradation. mTORC1, activated by post-prandial insulin and glucose, phosphorylates USP20 at S132 and S134, recruiting it to the HMGCR complex. Feeding-induced HMGCR stabilization is abolished in liver-specific Usp20-knockout and USP20(S132A/S134A) knock-in mice, and metabolic phenotypes are reversed by constitutively stable HMGCR(K248R).","method":"Genetic mouse models (liver-specific knockout, knock-in), in vivo feeding experiments, phosphorylation mapping, Co-IP, functional rescue with HMGCR(K248R)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal in vivo genetic models (KO, knock-in, rescue), Co-IP, phospho-site mutagenesis in a single rigorous study","pmids":["33177714"],"is_preprint":false},{"year":2019,"finding":"Among endogenous sterol intermediates of the mevalonate pathway, C4-dimethylated sterols (lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, dihydro-testis meiosis activating sterol) stimulate HMGCR degradation and inhibit SREBP-2 cleavage. Lanosterol specifically and selectively promotes HMGCR degradation without inhibiting SREBP-2 cleavage, establishing it as a bona fide endogenous regulator of HMGCR turnover.","method":"CRISPR/Cas9-mediated gene deletion of mevalonate pathway enzymes in HeLa cells expressing mevalonate transporter, lipidomics to measure sterol intermediates, HMGCR protein level assays","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR genetic engineering with multiple gene deletions, lipidomics, and direct protein-level readouts in a single rigorous study","pmids":["31455613"],"is_preprint":false},{"year":2017,"finding":"UBXD8 (UBX domain-containing protein 8) is an essential determinant of sterol-stimulated HMGCR degradation. UBXD8 is required for dislocation of ubiquitylated HMGCR from the ER membrane en route to proteasomal degradation, a function dependent on its UBX domain. UBXD8 ablation leads to aberrant cholesterol synthesis due to loss of feedback control.","method":"Unbiased haploid mammalian genetic screen using CRISPR/Cas9-tagged endogenous HMGCR-mNeon cells, UBXD8 knockdown/knockout in multiple cell types, UBX-domain mutagenesis, ER dislocation assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — unbiased genetic screen confirmed with domain mutagenesis and multiple cell-type knockouts in one study","pmids":["28882874"],"is_preprint":false},{"year":2013,"finding":"HNRNPA1 regulates HMGCR alternative splicing (exon 13 skipping) in an allele-dependent manner at rs3846662, which alters an HNRNPA1 binding motif. HNRNPA1 overexpression increases the ratio of HMGCR exon-13-skipping transcript, specifically stabilizes that isoform, and diminishes HMGCR enzyme activity while enhancing LDL-C uptake and increasing cellular apolipoprotein B.","method":"rs3846662 binding assay for HNRNPA1, sterol depletion/add-back experiments, HNRNPA1 overexpression in hepatoma cell lines, HMGCR enzyme activity assay, LDL-C uptake assay, clinical statin-response correlation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay, enzyme activity assay, and functional cellular readouts in one study with two independent clinical trial validations","pmids":["24001602"],"is_preprint":false},{"year":2008,"finding":"An intronic SNP in HMGCR (rs3846662) directly modulates alternative splicing of exon 13; the minor allele is associated with up to 2.2-fold lower expression of the alternatively spliced HMGCR transcript lacking exon 13. The exon-13-deleted splice variant cannot restore HMGCR activity when expressed in HMGCR-deficient UT-2 cells, indicating it encodes a non-functional enzyme.","method":"Minigene transfection assay, in vitro splicing in human lymphoblastoid cells, functional complementation in HMGCR-deficient UT-2 cells, GWAS with replication","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — minigene assay, functional complementation, and population genetics replication in one study","pmids":["18802019"],"is_preprint":false},{"year":2017,"finding":"Two sterol-regulatory elements (SREs) in close proximity exist in the human HMGCR promoter, along with one NF-Y binding site. HMGCR transcription is highly activated only when SREBP-2 levels are very high, in contrast to LDLR, ensuring preferential uptake of exogenous cholesterol before de novo synthesis is maximally induced.","method":"Luciferase reporter assays with SRE/NF-Y/Sp1 site mutant libraries, electrophoretic mobility shift assay (EMSA), ChIP-PCR","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — luciferase reporters, EMSA, and ChIP-PCR in one study with multiple orthogonal methods","pmids":["28342963"],"is_preprint":false},{"year":2024,"finding":"BRCC36 deubiquitinates HMGCR in a DUB-activity-dependent manner, inhibiting ferroptosis and promoting pyroptosis. HMGCR predominantly localizes to mitochondria during ferroptosis but shifts to the endoplasmic reticulum following pyroptosis induction. Thiolutin, a BRCC36 inhibitor, suppresses the BRCC36–HMGCR interaction.","method":"Co-IP, subcellular fractionation/localization (confocal microscopy), DUB activity assays, pharmacological inhibition with thiolutin, in vivo HCC xenograft","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with DUB assay and subcellular localization, single lab","pmids":["38178583"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, HMGCR pathway activity is required for cerebral-vascular stability via prenylation-dependent signaling. Cerebral hemorrhages induced by pharmacological or genetic HMGCR inhibition are rescued by exogenous geranylgeranyl pyrophosphate (GGPP), and mimicked by morpholino knockdown of GGTase I (geranylgeranyltransferase I β-subunit), implicating protein geranylgeranylation of Rho GTPases (including Cdc42) downstream of HMGCR.","method":"Pharmacological HMGCR inhibition (statins), genetic HMGCR knockdown, GGPP rescue supplementation, morpholino knockdown of GGTase I, endothelial Cdc42 expression analysis in zebrafish","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — pharmacological + genetic loss-of-function with specific metabolite rescue and downstream GTPase readout","pmids":["23206891"],"is_preprint":false},{"year":2009,"finding":"In Drosophila, the hmgcr-dependent isoprenoid pathway geranylates the G-protein γ-subunit Ggamma1, which is required for efficient release of the Hedgehog ligand from hh-expressing cells and for production of the germ cell attractant by somatic gonadal precursors. Trans-heterozygous combinations between ggamma1, hmgcr, and hh mutations disrupt germ cell migration, placing Ggamma1 downstream of Hmgcr in this pathway.","method":"Genetic epistasis (trans-heterozygous mutant combinations), loss- and gain-of-function ggamma1 experiments, dominant-negative non-geranylatable Ggamma1, ectopic hmgcr expression","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple allelic combinations and dominant-negative approach, replicated pathway placement","pmids":["19132091"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, the hedgehog pathway gene shifted (shf) cooperates with the hmgcr-dependent isoprenoid pathway to generate the germ cell attractant and to enhance the potency and long-range transmission of Hh from somatic gonadal precursors. The potentiation of Hh by ectopic hmgcr expression depends on cholesterol modification of Hh.","method":"Loss- and gain-of-function genetics (shf, hmgcr, hh), ectopic expression in nervous system, epistasis analysis, in vivo germ cell migration assay","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple conditions, single lab","pmids":["24068944"],"is_preprint":false},{"year":2019,"finding":"In Drosophila, the attractive signal for germ cell migration downstream of Hmgcr is cell-contact independent and acts at long range in a dose-dependent manner. This Hmgcr-mediated attraction does not require Wunens and operates independently of Hedgehog signaling, contradicting earlier proposals that Hh is the germ cell attractant downstream of Hmgcr.","method":"Quantitative germ cell migration assays, genetic epistasis (hmgcr, wunens, hh), tissue-specific expression experiments in Drosophila","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with quantitative readouts, single lab; contradicts prior model","pmids":["31719159"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, HMGCR expression in the corpus allatum (the gland where juvenile hormone is synthesized) is controlled by the insulin receptor (InR). Targeted RNAi against InR in the corpus allatum blocks both InR and HMGCR expression, while RNAi against HMGCR blocks only HMGCR; both disruptions cause loss of sexual dimorphism in locomotor activity and produce dwarf flies, placing HMGCR downstream of insulin signaling in JH biosynthesis.","method":"Tissue-specific RNAi (GAL4/UAS system) in Drosophila corpus allatum, locomotor activity assays, body size measurements","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific genetic knockdown with defined phenotypic readout, single lab","pmids":["17264888"],"is_preprint":false},{"year":2021,"finding":"In Tregs, loss of AMPKα1 promotes expression of HMGCR and glycolysis. AMPK activates p38 MAPK, which phosphorylates GSK-3β to inhibit PD-1 expression; mechanistically, HMGCR upregulation (downstream of AMPK loss) leads to elevated PD-1. Thus, AMPK suppresses PD-1 in Tregs via the HMGCR/p38 MAPK/GSK-3β signaling pathway.","method":"AMPKα1 conditional knockout in Tregs (AMPKα1fl/fl Foxp3YFP-Cre mice), western blotting, immunoprecipitation, immunofluorescence, flow cytometry","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with Co-IP and pathway dissection, single lab","pmids":["34649584"],"is_preprint":false},{"year":2018,"finding":"HSP90 physically interacts with HMGCR (co-immunoprecipitation) and regulates HMGCR protein levels by inhibiting its proteasomal degradation. Lovastatin (HMGCR inhibitor) impairs HSP90-dependent oncogenic functions (growth, migration, colony formation) in hepatocellular carcinoma cells.","method":"Immunoprecipitation, western blotting, lovastatin pharmacological inhibition, cell growth/migration assays","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, no domain mapping or reconstitution","pmids":["30483734"],"is_preprint":false},{"year":2021,"finding":"Under glucose-oxygen deprivation in human monocytes, HMGCR function is constrained, reducing GGPP synthesis; this decreases prenylation of the small GTPase Rac1, leading to increased binding of non-prenylated Rac1 to IQGAP1 and enhanced NLRP3 inflammasome activation and IL-1β release.","method":"GGPP measurement, Rac1 prenylation assay, IQGAP1 co-IP, NLRP3 inflammasome activation assay, IL-1β ELISA, primary patient monocytes (mevalonate kinase deficiency, Muckle-Wells syndrome) vs. controls","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with patient cells, Co-IP, and direct metabolite measurement, single lab","pmids":["39012939"],"is_preprint":false},{"year":2023,"finding":"Bi-allelic loss-of-function (amorphic) variants in HMGCR cause autosomal-recessive progressive limb-girdle muscular dystrophy. Protein activity studies of three variants (p.Asp623Asn, p.Tyr792Cys, p.Arg443Gln) confirmed decreased enzymatic activity and reduced protein stability, and molecular modeling showed the variants destabilize the protein and affect oligomerization.","method":"Exome sequencing, HMGCR enzyme activity assays, protein stability assays, molecular modeling, clinical phenotyping","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct enzymatic activity and stability assays on patient variants across five families with functional validation","pmids":["37167966"],"is_preprint":false},{"year":2023,"finding":"A homozygous missense loss-of-function mutation in HMGCR causes late-onset severe progressive limb-girdle muscular disease in humans. Oral mevalonolactone (the downstream mevalonate pathway product) is effective in treating this hereditary HMGCR myopathy in a patient and resolves statin-induced myopathy in mice, demonstrating that the myopathy results from deficient mevalonate pathway flux.","method":"Homozygosity mapping, whole exome sequencing, biochemical and biophysical functional analysis (confocal microscopy), biochemical synthesis of mevalonolactone, mouse statin myopathy model, human patient treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct functional analysis of patient mutation combined with therapeutic rescue in both mouse model and human patient","pmids":["36745799"],"is_preprint":false},{"year":2022,"finding":"SIAH1, an E3 ubiquitin ligase, ubiquitinates HMGCR and thereby reduces HMGCR protein levels, inhibiting cholesterol synthesis and efflux protein activity in lung cancer cells. SIAH1 overexpression or HMGCR knockdown retards tumor growth and enhances cisplatin efficacy in vivo.","method":"Co-IP/ubiquitination assay, SIAH1 overexpression, HMGCR knockdown, xenograft mouse model, cholesterol measurement","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination assay with E3 ligase identification and in vivo confirmation, single lab","pmids":["37062828"],"is_preprint":false},{"year":2021,"finding":"HMGCR inhibition (by statins or siRNA) in renal cell carcinoma leads to increased HSP90 expression, which stabilizes the glycolytic enzyme PKM2, thereby accelerating glycolysis and tumor growth. Suppressing glycolysis (via PKM2 inhibitor Shikonin) reverses the HMGCR inhibition-induced tumor growth acceleration.","method":"HMGCR siRNA knockdown, statin treatment, HSP90 expression measurement, PKM2 protein level and activity assays, RCC xenograft mouse model, Shikonin rescue","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with genetic and pharmacological tools plus in vivo rescue, single lab","pmids":["33905408"],"is_preprint":false},{"year":2021,"finding":"hnRNPR binds directly to the 3′-UTR of HMGCR mRNA via its RNA recognition motif (RRM), reducing HMGCR mRNA stability and translation, thereby decreasing HMGCR protein levels and neuronal cholesterol. HMGCR overexpression reverses the decrease in cholesterol caused by hnRNPR overexpression.","method":"RNA immunoprecipitation (RIP), luciferase reporter assay (3′-UTR), hnRNPR knockdown and overexpression in N2a and MN1 cells, cholesterol measurement, HMGCR rescue overexpression","journal":"Journal of integrative neuroscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct RNA–protein binding validated by RIP and luciferase, functional rescue, single lab","pmids":["34258925"],"is_preprint":false},{"year":2022,"finding":"lncRNA ZFAS1 stabilizes HMGCR mRNA by binding the RNA-binding protein U2AF2; U2AF2 in turn binds HMGCR mRNA and prevents its degradation, increasing HMGCR expression and promoting lipid accumulation in pancreatic carcinoma cells.","method":"RNA pulldown, RIP assay (ZFAS1–U2AF2 and U2AF2–HMGCR mRNA interactions), ZFAS1 gene knockout, U2AF2 and HMGCR knockdown, lipid content measurement","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNA pulldown and RIP validate direct interactions, functional KO, single lab","pmids":["35846429"],"is_preprint":false},{"year":2019,"finding":"Auranofin (anticancer gold compound) directly inhibits HMGCR enzymatic activity at micromolar IC50 levels. The auranofin-induced cancer cell death is partially reversed by downstream mevalonate pathway products (mevalonolactone or GGPP), indicating HMGCR inhibition contributes to its anticancer mechanism.","method":"In vitro HMGCR enzyme activity inhibition assay, mevalonolactone and GGPP rescue experiments, subcellular fractionation proteomics","journal":"Metallomics","confidence":"Medium","confidence_rationale":"Tier 1–3 / Moderate — direct in vitro enzyme inhibition with metabolite rescue, single lab","pmids":["31631207"],"is_preprint":false},{"year":2008,"finding":"CREM isoforms regulate the circadian expression of cholesterogenic genes in mouse liver; Hmgcr shows a phase advance (from CT20 to CT12) in Crem-knockout livers, and this corresponds to a phase advance in the lathosterol/cholesterol ratio. CREMtau and ICER have little effect on the Hmgcr proximal promoter, suggesting the circadian regulation of Hmgcr by CREM is indirect.","method":"Circadian expression profiling in Crem-knockout mice, GC-MS for sterol intermediates, promoter-reporter assays with CREMtau and ICER overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with metabolomics and reporter assays, single lab","pmids":["18775413"],"is_preprint":false},{"year":2012,"finding":"In weaning piglets, maternal low-protein diet induces HMGCR promoter hypomethylation, decreased histone H3 methylation (H3K9me1, H3K27me3) and increased H3 acetylation, which is associated with increased HMGCR mRNA expression and enzyme activity in the liver.","method":"Bisulfite sequencing/methylation analysis of HMGCR promoter, histone modification analysis (ChIP), HMGCR mRNA (qPCR), HMGCR enzyme activity assay in piglet liver","journal":"The Journal of nutritional biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter methylation and histone ChIP with enzyme activity, single lab in a pig model","pmids":["22444501"],"is_preprint":false},{"year":2022,"finding":"The S1P-induced proteolytic activation of SREBPs drives HMGCR expression in erythroblasts subjected to shear stress during differentiation; inhibition of S1P-mediated SREBP cleavage abolishes HMGCR upregulation and leads to erythroblast loss in dynamic culture, equivalent to lovastatin treatment.","method":"Shear stress experiments on primary human erythroblasts, S1P inhibition, lovastatin treatment, gene expression profiling, HMGCR protein quantification, osmotic resistance assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with mechanistic readout in primary human cells, single lab","pmids":["39627481"],"is_preprint":false},{"year":2014,"finding":"HMGCR (the rate-limiting enzyme of the mevalonate pathway) promotes gastric cancer cell growth and migration; knockdown inhibits growth, migration, and tumorigenesis. Mechanistically, HMGCR activates Hedgehog/Gli1 signaling and upregulates Gli1 target genes.","method":"HMGCR overexpression and shRNA knockdown in gastric cancer cells, cell growth/migration assays, in vivo tumorigenesis, Hedgehog/Gli1 pathway analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain- and loss-of-function with pathway readout, single lab","pmids":["27085483"],"is_preprint":false},{"year":2024,"finding":"In anti-HMGCR immune-mediated necrotizing myopathy, in vitro immunostaining on primary myotubes exposed to purified patient-derived anti-HMGCR autoantibodies reproduces the presence of HMGCR protein on altered myofibers, and sarcolemmal complement deposits (classical pathway activation) correlate with fiber necrosis (r=0.4, p=0.004), implicating antibody-mediated complement activation as a pathogenic mechanism.","method":"In vitro immunostaining with purified patient autoantibodies on primary myotubes, muscle biopsy immunostaining, correlation analysis of complement deposits and necrosis","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro autoantibody-myotube assay plus histological correlation, single study","pmids":["29330311"],"is_preprint":false}],"current_model":"HMGCR is the rate-limiting ER-resident enzyme that catalyzes HMG-CoA to mevalonate in the cholesterol and isoprenoid biosynthetic pathway; it is regulated at multiple levels including transcription (by SREBP-2 binding to two SREs in its promoter, requiring very high SREBP-2 levels), alternative splicing of exon 13 (modulated by HNRNPA1 at the rs3846662 SNP, with the exon-13-deleted isoform being enzymatically inactive), post-translational stabilization (by mTORC1-phosphorylated USP20 deubiquitylase in the fed state), and proteasomal degradation (triggered by endogenous lanosterol and other C4-dimethylated sterols, requiring UBXD8 for ER dislocation; additionally regulated by SIAH1 ubiquitination and BRCC36 deubiquitination); downstream, HMGCR-generated geranylgeranyl pyrophosphate supports prenylation of Rho-family GTPases (including Cdc42 and Rac1) to maintain vascular stability and suppress NLRP3 inflammasome activation, while in Drosophila the hmgcr-isoprenoid pathway geranylates Ggamma1 to control Hedgehog ligand release and germ cell migration."},"narrative":{"mechanistic_narrative":"HMGCR is the rate-limiting, ER-resident enzyme of the mevalonate pathway, and its activity is gated by an unusually dense network of transcriptional, splicing, and post-translational controls that match cholesterol and isoprenoid output to cellular demand [PMID:31455613, PMID:28342963]. Transcriptionally, HMGCR is induced by SREBP-2 acting on two closely spaced sterol-regulatory elements in its promoter, but only when SREBP-2 levels are very high, a threshold that favors uptake of exogenous LDL cholesterol over maximal de novo synthesis [PMID:28342963, PMID:39627481]. Output is tuned post-transcriptionally by allele-dependent skipping of exon 13 at rs3846662, governed by HNRNPA1, which yields an enzymatically inactive isoform [PMID:24001602, PMID:18802019], and by 3'-UTR-binding factors including hnRNPR that destabilize HMGCR mRNA [PMID:34258925]. Protein stability is the principal feedback node: endogenous C4-dimethylated sterols, lanosterol foremost, trigger ubiquitin-dependent degradation that requires UBXD8 for ER dislocation to the proteasome [PMID:31455613, PMID:28882874], while in the fed state mTORC1 phosphorylates the deubiquitylase USP20 to stabilize HMGCR and rescue metabolic phenotypes via the degradation-resistant K248R mutant [PMID:33177714]. The enzyme's principal output, geranylgeranyl pyrophosphate, sustains prenylation of Rho-family GTPases such as Cdc42 and Rac1, maintaining vascular stability and restraining NLRP3 inflammasome activation [PMID:23206891, PMID:39012939], and in Drosophila the same isoprenoid branch geranylates Ggamma1 to control long-range germ cell attraction and Hedgehog ligand release [PMID:19132091, PMID:24068944]. Bi-allelic loss-of-function variants in HMGCR cause autosomal-recessive progressive limb-girdle muscular dystrophy that reflects deficient mevalonate flux and is rescued by oral mevalonolactone [PMID:37167966, PMID:36745799].","teleology":[{"year":2008,"claim":"Established that a common intronic variant controls HMGCR output not by changing total expression alone but by directing production of a catalytically dead splice isoform, defining splicing as a tunable lever on enzyme activity.","evidence":"Minigene splicing assay and functional complementation of exon-13-deleted variant in HMGCR-deficient UT-2 cells with GWAS replication","pmids":["18802019"],"confidence":"High","gaps":["Did not identify the trans-acting splicing factor","Did not quantify the isoform's contribution to systemic cholesterol"]},{"year":2008,"claim":"Linked HMGCR expression to circadian timing, showing its phase tracks sterol-synthesis rhythms under CREM control, though indirectly.","evidence":"Circadian profiling in Crem-knockout mouse liver with GC-MS sterol measurement and promoter-reporter assays","pmids":["18775413"],"confidence":"Medium","gaps":["The intermediary linking CREM to Hmgcr is unidentified","Promoter reporters showed no direct CREM action"]},{"year":2013,"claim":"Identified HNRNPA1 as the allele-specific trans factor that drives exon-13 skipping at rs3846662, mechanistically connecting the SNP to reduced enzyme activity and altered LDL handling.","evidence":"rs3846662 binding assay, HNRNPA1 overexpression in hepatoma cells, enzyme activity and LDL-C uptake assays with clinical statin-response correlation","pmids":["24001602"],"confidence":"High","gaps":["Did not resolve how sterol status alters HNRNPA1 activity","Tissue-specificity of the splicing effect not mapped"]},{"year":2017,"claim":"Defined the transcriptional threshold logic of HMGCR induction, showing its two SREs respond only to very high SREBP-2, prioritizing exogenous cholesterol uptake over de novo synthesis.","evidence":"Luciferase reporter mutant libraries, EMSA, and ChIP-PCR on the human HMGCR promoter","pmids":["28342963"],"confidence":"High","gaps":["Did not address combinatorial input from other promoter factors in vivo","Did not connect threshold to physiological SREBP-2 ranges"]},{"year":2017,"claim":"Identified UBXD8 as the dislocation factor required to extract ubiquitylated HMGCR from the ER membrane, defining a discrete step in sterol-accelerated degradation.","evidence":"Unbiased haploid genetic screen on endogenous HMGCR-mNeon cells with UBX-domain mutagenesis and ER dislocation assays","pmids":["28882874"],"confidence":"High","gaps":["Did not identify the upstream E3 ligase coupling sterol sensing to HMGCR ubiquitination","Structural basis of dislocation unresolved"]},{"year":2019,"claim":"Pinpointed lanosterol and other C4-dimethylated sterols as the bona fide endogenous signals that selectively accelerate HMGCR turnover, separating degradation control from SREBP-2 cleavage control.","evidence":"CRISPR deletion of mevalonate-pathway enzymes in HeLa cells with lipidomics and protein-level readouts","pmids":["31455613"],"confidence":"High","gaps":["The direct sterol sensor for HMGCR degradation not isolated","Quantitative thresholds for in vivo regulation unknown"]},{"year":2020,"claim":"Closed the fed-state arm of HMGCR control by showing mTORC1-phosphorylated USP20 stabilizes HMGCR, with degradation-resistant HMGCR(K248R) reversing metabolic phenotypes, integrating nutrient signaling with cholesterol synthesis.","evidence":"Liver-specific Usp20 knockout, USP20(S132A/S134A) knock-in mice, phospho-site mapping, Co-IP, and HMGCR(K248R) rescue","pmids":["33177714"],"confidence":"High","gaps":["How USP20 recruitment integrates with the UBXD8/sterol degradation arm not resolved","Relevant E3 ligase counteracted by USP20 not defined in this study"]},{"year":2009,"claim":"Placed Hmgcr upstream of Ggamma1 geranylation in Drosophila, establishing that isoprenoid output, not sterol synthesis per se, generates a germ cell attractant and supports Hedgehog ligand release.","evidence":"Genetic epistasis with trans-heterozygous mutant combinations and dominant-negative non-geranylatable Ggamma1","pmids":["19132091"],"confidence":"High","gaps":["The identity of the secreted attractant remained unknown","Mammalian conservation of this branch not tested"]},{"year":2012,"claim":"Demonstrated that HMGCR-derived GGPP is required for vascular integrity via prenylation of Rho GTPases, providing a metabolite-rescue causal link in vivo.","evidence":"Pharmacological and genetic HMGCR inhibition in zebrafish with GGPP rescue, GGTase I morpholino knockdown, and endothelial Cdc42 analysis","pmids":["23206891"],"confidence":"High","gaps":["Did not resolve which prenylated GTPase is rate-limiting for vessel stability","Did not map effector signaling downstream of Cdc42"]},{"year":2019,"claim":"Refined the Drosophila germ cell model by showing Hmgcr-driven attraction acts at long range and dose-dependently and is independent of both Hedgehog and Wunens, revising the earlier attractant assignment.","evidence":"Quantitative germ cell migration assays with hmgcr, wunens, and hh genetic epistasis","pmids":["31719159"],"confidence":"Medium","gaps":["The molecular nature of the attractant remains unidentified","Single-lab finding contradicting prior model"]},{"year":2014,"claim":"Showed HMGCR can drive tumor growth via Hedgehog/Gli1 signaling in gastric cancer, extending its role beyond metabolism to oncogenic signaling.","evidence":"HMGCR overexpression and shRNA knockdown with tumorigenesis assays and Gli1 pathway analysis","pmids":["27085483"],"confidence":"Medium","gaps":["The metabolite linking HMGCR to Gli1 activation not defined","Single-lab and cancer-type specific"]},{"year":2021,"claim":"Connected HMGCR-derived GGPP supply to innate immunity, showing that reduced prenylation of Rac1 unleashes NLRP3 inflammasome activation through IQGAP1 binding.","evidence":"GGPP and Rac1 prenylation measurement, IQGAP1 Co-IP, and IL-1beta assays in patient monocytes","pmids":["39012939"],"confidence":"Medium","gaps":["Direct physiological triggers of HMGCR constraint not generalized beyond glucose-oxygen deprivation","Single-lab finding"]},{"year":2023,"claim":"Established HMGCR as a Mendelian disease gene by showing bi-allelic loss-of-function variants cause autosomal-recessive limb-girdle muscular dystrophy through reduced enzyme activity and stability, with mevalonolactone providing therapeutic rescue.","evidence":"Exome sequencing across families, enzyme activity and stability assays on patient variants, molecular modeling, and mevalonolactone treatment in patient and statin-myopathy mouse model","pmids":["37167966","36745799"],"confidence":"High","gaps":["Why muscle is selectively vulnerable to mevalonate deficiency not fully explained","Long-term efficacy of mevalonolactone not established"]},{"year":2022,"claim":"Catalogued additional ubiquitin-system and RNA-binding regulators (SIAH1, BRCC36, hnRNPR, ZFAS1/U2AF2) that fine-tune HMGCR levels in disease contexts, broadening the regulatory map.","evidence":"Co-IP/ubiquitination assays, RIP and RNA pulldown, and knockdown/knockout with lipid and tumor readouts across cancer models","pmids":["37062828","38178583","34258925","35846429"],"confidence":"Medium","gaps":["These regulators are largely demonstrated in single labs and specific cancer cells","Integration with the canonical sterol-degradation machinery not established"]},{"year":null,"claim":"The direct sterol sensor and the full E3 ligase set that couple lanosterol detection to HMGCR ubiquitination, and the molecular identity of the Drosophila Hmgcr-dependent germ cell attractant, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No isolated direct sterol receptor for degradation","Attractant downstream of Hmgcr unidentified","Relationship among USP20, SIAH1, BRCC36, and UBXD8 in vivo unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,15,16,21]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,16]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,5,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,14,25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,26]}],"complexes":[],"partners":["USP20","UBXD8","HNRNPA1","BRCC36","SIAH1","HSP90","HNRNPR","U2AF2"],"other_free_text":[]}},"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). 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risk.","date":"2011","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/21867541","citation_count":10,"is_preprint":false},{"pmid":"31301429","id":"PMC_31301429","title":"cDNA cloning, prokaryotic expression and functional analysis of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in Pogostemon cablin.","date":"2019","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/31301429","citation_count":9,"is_preprint":false},{"pmid":"26301579","id":"PMC_26301579","title":"Association between the Lipid Levels and Single Nucleotide Polymorphisms of ABCA1, APOE and HMGCR Genes in Subjects with Spontaneous Preterm Delivery.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26301579","citation_count":9,"is_preprint":false},{"pmid":"34258925","id":"PMC_34258925","title":"RNA-binding protein hnRNPR reduces neuronal cholesterol levels by binding to and suppressing HMGCR.","date":"2021","source":"Journal of integrative neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34258925","citation_count":8,"is_preprint":false},{"pmid":"31719159","id":"PMC_31719159","title":"Hmgcr promotes a long-range signal to attract Drosophila germ cells independently of Hedgehog.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31719159","citation_count":8,"is_preprint":false},{"pmid":"26541602","id":"PMC_26541602","title":"Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology.","date":"2015","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/26541602","citation_count":8,"is_preprint":false},{"pmid":"32241558","id":"PMC_32241558","title":"Transthyretin Regulated by linc00657/miR-205-5p Promoted Cholesterol Metabolism by Inducing SREBP2-HMGCR and Inhibiting LXRα-CYP7A1.","date":"2020","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/32241558","citation_count":8,"is_preprint":false},{"pmid":"39106428","id":"PMC_39106428","title":"Absence of Pathogenic Mutations and Strong Association With HLA-DRB1*11:01 in Statin-Naïve Early-Onset Anti-HMGCR Necrotizing Myopathy.","date":"2024","source":"Neurology(R) neuroimmunology & neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/39106428","citation_count":8,"is_preprint":false},{"pmid":"19327767","id":"PMC_19327767","title":"Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome.","date":"2009","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/19327767","citation_count":8,"is_preprint":false},{"pmid":"30461626","id":"PMC_30461626","title":"Coexistence of anti-HMGCR and anti-MDA5 identified by an unlabeled immunoprecipitation assay in a chinese patient cohort with myositis.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30461626","citation_count":8,"is_preprint":false},{"pmid":"40347460","id":"PMC_40347460","title":"The incidence of anti-HMGCR immune-mediated necrotizing myopathy: an Australian and UK retrospective multi-site cohort study.","date":"2025","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40347460","citation_count":7,"is_preprint":false},{"pmid":"29439058","id":"PMC_29439058","title":"Autoimmune necrotising myopathy and HMGCR antibodies.","date":"2018","source":"Practical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29439058","citation_count":7,"is_preprint":false},{"pmid":"31212640","id":"PMC_31212640","title":"Porcine HMGCR Inhibits Porcine Circovirus Type 2 Infection by Directly Interacting with the Viral 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rats.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37916105","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53011,"output_tokens":7309,"usd":0.134334,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16501,"output_tokens":4634,"usd":0.099178,"stage2_stop_reason":"end_turn"},"total_usd":0.233512,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"The deubiquitylase USP20 stabilizes HMGCR in the fed state by antagonizing its ubiquitin-dependent degradation. mTORC1, activated by post-prandial insulin and glucose, phosphorylates USP20 at S132 and S134, recruiting it to the HMGCR complex. Feeding-induced HMGCR stabilization is abolished in liver-specific Usp20-knockout and USP20(S132A/S134A) knock-in mice, and metabolic phenotypes are reversed by constitutively stable HMGCR(K248R).\",\n      \"method\": \"Genetic mouse models (liver-specific knockout, knock-in), in vivo feeding experiments, phosphorylation mapping, Co-IP, functional rescue with HMGCR(K248R)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal in vivo genetic models (KO, knock-in, rescue), Co-IP, phospho-site mutagenesis in a single rigorous study\",\n      \"pmids\": [\"33177714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Among endogenous sterol intermediates of the mevalonate pathway, C4-dimethylated sterols (lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, dihydro-testis meiosis activating sterol) stimulate HMGCR degradation and inhibit SREBP-2 cleavage. Lanosterol specifically and selectively promotes HMGCR degradation without inhibiting SREBP-2 cleavage, establishing it as a bona fide endogenous regulator of HMGCR turnover.\",\n      \"method\": \"CRISPR/Cas9-mediated gene deletion of mevalonate pathway enzymes in HeLa cells expressing mevalonate transporter, lipidomics to measure sterol intermediates, HMGCR protein level assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR genetic engineering with multiple gene deletions, lipidomics, and direct protein-level readouts in a single rigorous study\",\n      \"pmids\": [\"31455613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBXD8 (UBX domain-containing protein 8) is an essential determinant of sterol-stimulated HMGCR degradation. UBXD8 is required for dislocation of ubiquitylated HMGCR from the ER membrane en route to proteasomal degradation, a function dependent on its UBX domain. UBXD8 ablation leads to aberrant cholesterol synthesis due to loss of feedback control.\",\n      \"method\": \"Unbiased haploid mammalian genetic screen using CRISPR/Cas9-tagged endogenous HMGCR-mNeon cells, UBXD8 knockdown/knockout in multiple cell types, UBX-domain mutagenesis, ER dislocation assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — unbiased genetic screen confirmed with domain mutagenesis and multiple cell-type knockouts in one study\",\n      \"pmids\": [\"28882874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HNRNPA1 regulates HMGCR alternative splicing (exon 13 skipping) in an allele-dependent manner at rs3846662, which alters an HNRNPA1 binding motif. HNRNPA1 overexpression increases the ratio of HMGCR exon-13-skipping transcript, specifically stabilizes that isoform, and diminishes HMGCR enzyme activity while enhancing LDL-C uptake and increasing cellular apolipoprotein B.\",\n      \"method\": \"rs3846662 binding assay for HNRNPA1, sterol depletion/add-back experiments, HNRNPA1 overexpression in hepatoma cell lines, HMGCR enzyme activity assay, LDL-C uptake assay, clinical statin-response correlation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay, enzyme activity assay, and functional cellular readouts in one study with two independent clinical trial validations\",\n      \"pmids\": [\"24001602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"An intronic SNP in HMGCR (rs3846662) directly modulates alternative splicing of exon 13; the minor allele is associated with up to 2.2-fold lower expression of the alternatively spliced HMGCR transcript lacking exon 13. The exon-13-deleted splice variant cannot restore HMGCR activity when expressed in HMGCR-deficient UT-2 cells, indicating it encodes a non-functional enzyme.\",\n      \"method\": \"Minigene transfection assay, in vitro splicing in human lymphoblastoid cells, functional complementation in HMGCR-deficient UT-2 cells, GWAS with replication\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — minigene assay, functional complementation, and population genetics replication in one study\",\n      \"pmids\": [\"18802019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Two sterol-regulatory elements (SREs) in close proximity exist in the human HMGCR promoter, along with one NF-Y binding site. HMGCR transcription is highly activated only when SREBP-2 levels are very high, in contrast to LDLR, ensuring preferential uptake of exogenous cholesterol before de novo synthesis is maximally induced.\",\n      \"method\": \"Luciferase reporter assays with SRE/NF-Y/Sp1 site mutant libraries, 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 1–2 / Moderate — luciferase reporters, EMSA, and ChIP-PCR in one study with multiple orthogonal methods\",\n      \"pmids\": [\"28342963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRCC36 deubiquitinates HMGCR in a DUB-activity-dependent manner, inhibiting ferroptosis and promoting pyroptosis. HMGCR predominantly localizes to mitochondria during ferroptosis but shifts to the endoplasmic reticulum following pyroptosis induction. Thiolutin, a BRCC36 inhibitor, suppresses the BRCC36–HMGCR interaction.\",\n      \"method\": \"Co-IP, subcellular fractionation/localization (confocal microscopy), DUB activity assays, pharmacological inhibition with thiolutin, in vivo HCC xenograft\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with DUB assay and subcellular localization, single lab\",\n      \"pmids\": [\"38178583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, HMGCR pathway activity is required for cerebral-vascular stability via prenylation-dependent signaling. Cerebral hemorrhages induced by pharmacological or genetic HMGCR inhibition are rescued by exogenous geranylgeranyl pyrophosphate (GGPP), and mimicked by morpholino knockdown of GGTase I (geranylgeranyltransferase I β-subunit), implicating protein geranylgeranylation of Rho GTPases (including Cdc42) downstream of HMGCR.\",\n      \"method\": \"Pharmacological HMGCR inhibition (statins), genetic HMGCR knockdown, GGPP rescue supplementation, morpholino knockdown of GGTase I, endothelial Cdc42 expression analysis in zebrafish\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — pharmacological + genetic loss-of-function with specific metabolite rescue and downstream GTPase readout\",\n      \"pmids\": [\"23206891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Drosophila, the hmgcr-dependent isoprenoid pathway geranylates the G-protein γ-subunit Ggamma1, which is required for efficient release of the Hedgehog ligand from hh-expressing cells and for production of the germ cell attractant by somatic gonadal precursors. Trans-heterozygous combinations between ggamma1, hmgcr, and hh mutations disrupt germ cell migration, placing Ggamma1 downstream of Hmgcr in this pathway.\",\n      \"method\": \"Genetic epistasis (trans-heterozygous mutant combinations), loss- and gain-of-function ggamma1 experiments, dominant-negative non-geranylatable Ggamma1, ectopic hmgcr expression\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple allelic combinations and dominant-negative approach, replicated pathway placement\",\n      \"pmids\": [\"19132091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, the hedgehog pathway gene shifted (shf) cooperates with the hmgcr-dependent isoprenoid pathway to generate the germ cell attractant and to enhance the potency and long-range transmission of Hh from somatic gonadal precursors. The potentiation of Hh by ectopic hmgcr expression depends on cholesterol modification of Hh.\",\n      \"method\": \"Loss- and gain-of-function genetics (shf, hmgcr, hh), ectopic expression in nervous system, epistasis analysis, in vivo germ cell migration assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple conditions, single lab\",\n      \"pmids\": [\"24068944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila, the attractive signal for germ cell migration downstream of Hmgcr is cell-contact independent and acts at long range in a dose-dependent manner. This Hmgcr-mediated attraction does not require Wunens and operates independently of Hedgehog signaling, contradicting earlier proposals that Hh is the germ cell attractant downstream of Hmgcr.\",\n      \"method\": \"Quantitative germ cell migration assays, genetic epistasis (hmgcr, wunens, hh), tissue-specific expression experiments in Drosophila\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with quantitative readouts, single lab; contradicts prior model\",\n      \"pmids\": [\"31719159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, HMGCR expression in the corpus allatum (the gland where juvenile hormone is synthesized) is controlled by the insulin receptor (InR). Targeted RNAi against InR in the corpus allatum blocks both InR and HMGCR expression, while RNAi against HMGCR blocks only HMGCR; both disruptions cause loss of sexual dimorphism in locomotor activity and produce dwarf flies, placing HMGCR downstream of insulin signaling in JH biosynthesis.\",\n      \"method\": \"Tissue-specific RNAi (GAL4/UAS system) in Drosophila corpus allatum, locomotor activity assays, body size measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific genetic knockdown with defined phenotypic readout, single lab\",\n      \"pmids\": [\"17264888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Tregs, loss of AMPKα1 promotes expression of HMGCR and glycolysis. AMPK activates p38 MAPK, which phosphorylates GSK-3β to inhibit PD-1 expression; mechanistically, HMGCR upregulation (downstream of AMPK loss) leads to elevated PD-1. Thus, AMPK suppresses PD-1 in Tregs via the HMGCR/p38 MAPK/GSK-3β signaling pathway.\",\n      \"method\": \"AMPKα1 conditional knockout in Tregs (AMPKα1fl/fl Foxp3YFP-Cre mice), western blotting, immunoprecipitation, immunofluorescence, flow cytometry\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with Co-IP and pathway dissection, single lab\",\n      \"pmids\": [\"34649584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HSP90 physically interacts with HMGCR (co-immunoprecipitation) and regulates HMGCR protein levels by inhibiting its proteasomal degradation. Lovastatin (HMGCR inhibitor) impairs HSP90-dependent oncogenic functions (growth, migration, colony formation) in hepatocellular carcinoma cells.\",\n      \"method\": \"Immunoprecipitation, western blotting, lovastatin pharmacological inhibition, cell growth/migration assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, no domain mapping or reconstitution\",\n      \"pmids\": [\"30483734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Under glucose-oxygen deprivation in human monocytes, HMGCR function is constrained, reducing GGPP synthesis; this decreases prenylation of the small GTPase Rac1, leading to increased binding of non-prenylated Rac1 to IQGAP1 and enhanced NLRP3 inflammasome activation and IL-1β release.\",\n      \"method\": \"GGPP measurement, Rac1 prenylation assay, IQGAP1 co-IP, NLRP3 inflammasome activation assay, IL-1β ELISA, primary patient monocytes (mevalonate kinase deficiency, Muckle-Wells syndrome) vs. controls\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with patient cells, Co-IP, and direct metabolite measurement, single lab\",\n      \"pmids\": [\"39012939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bi-allelic loss-of-function (amorphic) variants in HMGCR cause autosomal-recessive progressive limb-girdle muscular dystrophy. Protein activity studies of three variants (p.Asp623Asn, p.Tyr792Cys, p.Arg443Gln) confirmed decreased enzymatic activity and reduced protein stability, and molecular modeling showed the variants destabilize the protein and affect oligomerization.\",\n      \"method\": \"Exome sequencing, HMGCR enzyme activity assays, protein stability assays, molecular modeling, clinical phenotyping\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct enzymatic activity and stability assays on patient variants across five families with functional validation\",\n      \"pmids\": [\"37167966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A homozygous missense loss-of-function mutation in HMGCR causes late-onset severe progressive limb-girdle muscular disease in humans. Oral mevalonolactone (the downstream mevalonate pathway product) is effective in treating this hereditary HMGCR myopathy in a patient and resolves statin-induced myopathy in mice, demonstrating that the myopathy results from deficient mevalonate pathway flux.\",\n      \"method\": \"Homozygosity mapping, whole exome sequencing, biochemical and biophysical functional analysis (confocal microscopy), biochemical synthesis of mevalonolactone, mouse statin myopathy model, human patient treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct functional analysis of patient mutation combined with therapeutic rescue in both mouse model and human patient\",\n      \"pmids\": [\"36745799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIAH1, an E3 ubiquitin ligase, ubiquitinates HMGCR and thereby reduces HMGCR protein levels, inhibiting cholesterol synthesis and efflux protein activity in lung cancer cells. SIAH1 overexpression or HMGCR knockdown retards tumor growth and enhances cisplatin efficacy in vivo.\",\n      \"method\": \"Co-IP/ubiquitination assay, SIAH1 overexpression, HMGCR knockdown, xenograft mouse model, cholesterol measurement\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination assay with E3 ligase identification and in vivo confirmation, single lab\",\n      \"pmids\": [\"37062828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HMGCR inhibition (by statins or siRNA) in renal cell carcinoma leads to increased HSP90 expression, which stabilizes the glycolytic enzyme PKM2, thereby accelerating glycolysis and tumor growth. Suppressing glycolysis (via PKM2 inhibitor Shikonin) reverses the HMGCR inhibition-induced tumor growth acceleration.\",\n      \"method\": \"HMGCR siRNA knockdown, statin treatment, HSP90 expression measurement, PKM2 protein level and activity assays, RCC xenograft mouse model, Shikonin rescue\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with genetic and pharmacological tools plus in vivo rescue, single lab\",\n      \"pmids\": [\"33905408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hnRNPR binds directly to the 3′-UTR of HMGCR mRNA via its RNA recognition motif (RRM), reducing HMGCR mRNA stability and translation, thereby decreasing HMGCR protein levels and neuronal cholesterol. HMGCR overexpression reverses the decrease in cholesterol caused by hnRNPR overexpression.\",\n      \"method\": \"RNA immunoprecipitation (RIP), luciferase reporter assay (3′-UTR), hnRNPR knockdown and overexpression in N2a and MN1 cells, cholesterol measurement, HMGCR rescue overexpression\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct RNA–protein binding validated by RIP and luciferase, functional rescue, single lab\",\n      \"pmids\": [\"34258925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"lncRNA ZFAS1 stabilizes HMGCR mRNA by binding the RNA-binding protein U2AF2; U2AF2 in turn binds HMGCR mRNA and prevents its degradation, increasing HMGCR expression and promoting lipid accumulation in pancreatic carcinoma cells.\",\n      \"method\": \"RNA pulldown, RIP assay (ZFAS1–U2AF2 and U2AF2–HMGCR mRNA interactions), ZFAS1 gene knockout, U2AF2 and HMGCR knockdown, lipid content measurement\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNA pulldown and RIP validate direct interactions, functional KO, single lab\",\n      \"pmids\": [\"35846429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Auranofin (anticancer gold compound) directly inhibits HMGCR enzymatic activity at micromolar IC50 levels. The auranofin-induced cancer cell death is partially reversed by downstream mevalonate pathway products (mevalonolactone or GGPP), indicating HMGCR inhibition contributes to its anticancer mechanism.\",\n      \"method\": \"In vitro HMGCR enzyme activity inhibition assay, mevalonolactone and GGPP rescue experiments, subcellular fractionation proteomics\",\n      \"journal\": \"Metallomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–3 / Moderate — direct in vitro enzyme inhibition with metabolite rescue, single lab\",\n      \"pmids\": [\"31631207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CREM isoforms regulate the circadian expression of cholesterogenic genes in mouse liver; Hmgcr shows a phase advance (from CT20 to CT12) in Crem-knockout livers, and this corresponds to a phase advance in the lathosterol/cholesterol ratio. CREMtau and ICER have little effect on the Hmgcr proximal promoter, suggesting the circadian regulation of Hmgcr by CREM is indirect.\",\n      \"method\": \"Circadian expression profiling in Crem-knockout mice, GC-MS for sterol intermediates, promoter-reporter assays with CREMtau and ICER overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with metabolomics and reporter assays, single lab\",\n      \"pmids\": [\"18775413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In weaning piglets, maternal low-protein diet induces HMGCR promoter hypomethylation, decreased histone H3 methylation (H3K9me1, H3K27me3) and increased H3 acetylation, which is associated with increased HMGCR mRNA expression and enzyme activity in the liver.\",\n      \"method\": \"Bisulfite sequencing/methylation analysis of HMGCR promoter, histone modification analysis (ChIP), HMGCR mRNA (qPCR), HMGCR enzyme activity assay in piglet liver\",\n      \"journal\": \"The Journal of nutritional biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter methylation and histone ChIP with enzyme activity, single lab in a pig model\",\n      \"pmids\": [\"22444501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The S1P-induced proteolytic activation of SREBPs drives HMGCR expression in erythroblasts subjected to shear stress during differentiation; inhibition of S1P-mediated SREBP cleavage abolishes HMGCR upregulation and leads to erythroblast loss in dynamic culture, equivalent to lovastatin treatment.\",\n      \"method\": \"Shear stress experiments on primary human erythroblasts, S1P inhibition, lovastatin treatment, gene expression profiling, HMGCR protein quantification, osmotic resistance assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with mechanistic readout in primary human cells, single lab\",\n      \"pmids\": [\"39627481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HMGCR (the rate-limiting enzyme of the mevalonate pathway) promotes gastric cancer cell growth and migration; knockdown inhibits growth, migration, and tumorigenesis. Mechanistically, HMGCR activates Hedgehog/Gli1 signaling and upregulates Gli1 target genes.\",\n      \"method\": \"HMGCR overexpression and shRNA knockdown in gastric cancer cells, cell growth/migration assays, in vivo tumorigenesis, Hedgehog/Gli1 pathway analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain- and loss-of-function with pathway readout, single lab\",\n      \"pmids\": [\"27085483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In anti-HMGCR immune-mediated necrotizing myopathy, in vitro immunostaining on primary myotubes exposed to purified patient-derived anti-HMGCR autoantibodies reproduces the presence of HMGCR protein on altered myofibers, and sarcolemmal complement deposits (classical pathway activation) correlate with fiber necrosis (r=0.4, p=0.004), implicating antibody-mediated complement activation as a pathogenic mechanism.\",\n      \"method\": \"In vitro immunostaining with purified patient autoantibodies on primary myotubes, muscle biopsy immunostaining, correlation analysis of complement deposits and necrosis\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro autoantibody-myotube assay plus histological correlation, single study\",\n      \"pmids\": [\"29330311\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMGCR is the rate-limiting ER-resident enzyme that catalyzes HMG-CoA to mevalonate in the cholesterol and isoprenoid biosynthetic pathway; it is regulated at multiple levels including transcription (by SREBP-2 binding to two SREs in its promoter, requiring very high SREBP-2 levels), alternative splicing of exon 13 (modulated by HNRNPA1 at the rs3846662 SNP, with the exon-13-deleted isoform being enzymatically inactive), post-translational stabilization (by mTORC1-phosphorylated USP20 deubiquitylase in the fed state), and proteasomal degradation (triggered by endogenous lanosterol and other C4-dimethylated sterols, requiring UBXD8 for ER dislocation; additionally regulated by SIAH1 ubiquitination and BRCC36 deubiquitination); downstream, HMGCR-generated geranylgeranyl pyrophosphate supports prenylation of Rho-family GTPases (including Cdc42 and Rac1) to maintain vascular stability and suppress NLRP3 inflammasome activation, while in Drosophila the hmgcr-isoprenoid pathway geranylates Ggamma1 to control Hedgehog ligand release and germ cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HMGCR is the rate-limiting, ER-resident enzyme of the mevalonate pathway, and its activity is gated by an unusually dense network of transcriptional, splicing, and post-translational controls that match cholesterol and isoprenoid output to cellular demand [#1, #5]. Transcriptionally, HMGCR is induced by SREBP-2 acting on two closely spaced sterol-regulatory elements in its promoter, but only when SREBP-2 levels are very high, a threshold that favors uptake of exogenous LDL cholesterol over maximal de novo synthesis [#5, #24]. Output is tuned post-transcriptionally by allele-dependent skipping of exon 13 at rs3846662, governed by HNRNPA1, which yields an enzymatically inactive isoform [#3, #4], and by 3'-UTR-binding factors including hnRNPR that destabilize HMGCR mRNA [#19]. Protein stability is the principal feedback node: endogenous C4-dimethylated sterols, lanosterol foremost, trigger ubiquitin-dependent degradation that requires UBXD8 for ER dislocation to the proteasome [#1, #2], while in the fed state mTORC1 phosphorylates the deubiquitylase USP20 to stabilize HMGCR and rescue metabolic phenotypes via the degradation-resistant K248R mutant [#0]. The enzyme's principal output, geranylgeranyl pyrophosphate, sustains prenylation of Rho-family GTPases such as Cdc42 and Rac1, maintaining vascular stability and restraining NLRP3 inflammasome activation [#7, #14], and in Drosophila the same isoprenoid branch geranylates Ggamma1 to control long-range germ cell attraction and Hedgehog ligand release [#8, #9]. Bi-allelic loss-of-function variants in HMGCR cause autosomal-recessive progressive limb-girdle muscular dystrophy that reflects deficient mevalonate flux and is rescued by oral mevalonolactone [#15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that a common intronic variant controls HMGCR output not by changing total expression alone but by directing production of a catalytically dead splice isoform, defining splicing as a tunable lever on enzyme activity.\",\n      \"evidence\": \"Minigene splicing assay and functional complementation of exon-13-deleted variant in HMGCR-deficient UT-2 cells with GWAS replication\",\n      \"pmids\": [\"18802019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the trans-acting splicing factor\", \"Did not quantify the isoform's contribution to systemic cholesterol\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked HMGCR expression to circadian timing, showing its phase tracks sterol-synthesis rhythms under CREM control, though indirectly.\",\n      \"evidence\": \"Circadian profiling in Crem-knockout mouse liver with GC-MS sterol measurement and promoter-reporter assays\",\n      \"pmids\": [\"18775413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The intermediary linking CREM to Hmgcr is unidentified\", \"Promoter reporters showed no direct CREM action\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified HNRNPA1 as the allele-specific trans factor that drives exon-13 skipping at rs3846662, mechanistically connecting the SNP to reduced enzyme activity and altered LDL handling.\",\n      \"evidence\": \"rs3846662 binding assay, HNRNPA1 overexpression in hepatoma cells, enzyme activity and LDL-C uptake assays with clinical statin-response correlation\",\n      \"pmids\": [\"24001602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how sterol status alters HNRNPA1 activity\", \"Tissue-specificity of the splicing effect not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the transcriptional threshold logic of HMGCR induction, showing its two SREs respond only to very high SREBP-2, prioritizing exogenous cholesterol uptake over de novo synthesis.\",\n      \"evidence\": \"Luciferase reporter mutant libraries, EMSA, and ChIP-PCR on the human HMGCR promoter\",\n      \"pmids\": [\"28342963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address combinatorial input from other promoter factors in vivo\", \"Did not connect threshold to physiological SREBP-2 ranges\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified UBXD8 as the dislocation factor required to extract ubiquitylated HMGCR from the ER membrane, defining a discrete step in sterol-accelerated degradation.\",\n      \"evidence\": \"Unbiased haploid genetic screen on endogenous HMGCR-mNeon cells with UBX-domain mutagenesis and ER dislocation assays\",\n      \"pmids\": [\"28882874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the upstream E3 ligase coupling sterol sensing to HMGCR ubiquitination\", \"Structural basis of dislocation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed lanosterol and other C4-dimethylated sterols as the bona fide endogenous signals that selectively accelerate HMGCR turnover, separating degradation control from SREBP-2 cleavage control.\",\n      \"evidence\": \"CRISPR deletion of mevalonate-pathway enzymes in HeLa cells with lipidomics and protein-level readouts\",\n      \"pmids\": [\"31455613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct sterol sensor for HMGCR degradation not isolated\", \"Quantitative thresholds for in vivo regulation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Closed the fed-state arm of HMGCR control by showing mTORC1-phosphorylated USP20 stabilizes HMGCR, with degradation-resistant HMGCR(K248R) reversing metabolic phenotypes, integrating nutrient signaling with cholesterol synthesis.\",\n      \"evidence\": \"Liver-specific Usp20 knockout, USP20(S132A/S134A) knock-in mice, phospho-site mapping, Co-IP, and HMGCR(K248R) rescue\",\n      \"pmids\": [\"33177714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP20 recruitment integrates with the UBXD8/sterol degradation arm not resolved\", \"Relevant E3 ligase counteracted by USP20 not defined in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed Hmgcr upstream of Ggamma1 geranylation in Drosophila, establishing that isoprenoid output, not sterol synthesis per se, generates a germ cell attractant and supports Hedgehog ligand release.\",\n      \"evidence\": \"Genetic epistasis with trans-heterozygous mutant combinations and dominant-negative non-geranylatable Ggamma1\",\n      \"pmids\": [\"19132091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The identity of the secreted attractant remained unknown\", \"Mammalian conservation of this branch not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that HMGCR-derived GGPP is required for vascular integrity via prenylation of Rho GTPases, providing a metabolite-rescue causal link in vivo.\",\n      \"evidence\": \"Pharmacological and genetic HMGCR inhibition in zebrafish with GGPP rescue, GGTase I morpholino knockdown, and endothelial Cdc42 analysis\",\n      \"pmids\": [\"23206891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which prenylated GTPase is rate-limiting for vessel stability\", \"Did not map effector signaling downstream of Cdc42\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the Drosophila germ cell model by showing Hmgcr-driven attraction acts at long range and dose-dependently and is independent of both Hedgehog and Wunens, revising the earlier attractant assignment.\",\n      \"evidence\": \"Quantitative germ cell migration assays with hmgcr, wunens, and hh genetic epistasis\",\n      \"pmids\": [\"31719159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular nature of the attractant remains unidentified\", \"Single-lab finding contradicting prior model\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed HMGCR can drive tumor growth via Hedgehog/Gli1 signaling in gastric cancer, extending its role beyond metabolism to oncogenic signaling.\",\n      \"evidence\": \"HMGCR overexpression and shRNA knockdown with tumorigenesis assays and Gli1 pathway analysis\",\n      \"pmids\": [\"27085483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The metabolite linking HMGCR to Gli1 activation not defined\", \"Single-lab and cancer-type specific\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected HMGCR-derived GGPP supply to innate immunity, showing that reduced prenylation of Rac1 unleashes NLRP3 inflammasome activation through IQGAP1 binding.\",\n      \"evidence\": \"GGPP and Rac1 prenylation measurement, IQGAP1 Co-IP, and IL-1beta assays in patient monocytes\",\n      \"pmids\": [\"39012939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physiological triggers of HMGCR constraint not generalized beyond glucose-oxygen deprivation\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established HMGCR as a Mendelian disease gene by showing bi-allelic loss-of-function variants cause autosomal-recessive limb-girdle muscular dystrophy through reduced enzyme activity and stability, with mevalonolactone providing therapeutic rescue.\",\n      \"evidence\": \"Exome sequencing across families, enzyme activity and stability assays on patient variants, molecular modeling, and mevalonolactone treatment in patient and statin-myopathy mouse model\",\n      \"pmids\": [\"37167966\", \"36745799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why muscle is selectively vulnerable to mevalonate deficiency not fully explained\", \"Long-term efficacy of mevalonolactone not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Catalogued additional ubiquitin-system and RNA-binding regulators (SIAH1, BRCC36, hnRNPR, ZFAS1/U2AF2) that fine-tune HMGCR levels in disease contexts, broadening the regulatory map.\",\n      \"evidence\": \"Co-IP/ubiquitination assays, RIP and RNA pulldown, and knockdown/knockout with lipid and tumor readouts across cancer models\",\n      \"pmids\": [\"37062828\", \"38178583\", \"34258925\", \"35846429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"These regulators are largely demonstrated in single labs and specific cancer cells\", \"Integration with the canonical sterol-degradation machinery not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct sterol sensor and the full E3 ligase set that couple lanosterol detection to HMGCR ubiquitination, and the molecular identity of the Drosophila Hmgcr-dependent germ cell attractant, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No isolated direct sterol receptor for degradation\", \"Attractant downstream of Hmgcr unidentified\", \"Relationship among USP20, SIAH1, BRCC36, and UBXD8 in vivo unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 15, 16, 21]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 5, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 14, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"USP20\", \"UBXD8\", \"HNRNPA1\", \"BRCC36\", \"SIAH1\", \"HSP90\", \"hnRNPR\", \"U2AF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}