{"gene":"HMGCS1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2011,"finding":"SIRT1 deacetylates HMGCS1 in the cytoplasm, establishing HMGCS1 as a substrate for the cytoplasmic deacetylase SIRT1 (analogous to the SIRT3/HMGCS2 pair in mitochondria).","method":"Deacetylation assay; evolutionary/substrate homology analysis","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, reported as direct deacetylation but abstract is brief and lacks full methodological detail; supported by parallel AceCS1/2 and HMGCS2/SIRT3 paradigm","pmids":["21701047"],"is_preprint":false},{"year":2017,"finding":"Knockdown of HMGCS1 by shRNA significantly reduces prostate cancer cell viability, and exogenous overexpression of HMGCS1 in prostate cancer or stromal cells stimulates cancer cell growth, demonstrating a functional role via autocrine/paracrine mevalonate pathway activity.","method":"shRNA knockdown, overexpression, cell viability assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype, single lab, two complementary approaches","pmids":["29163687"],"is_preprint":false},{"year":2020,"finding":"KLF13 transcriptionally inhibits HMGCS1 expression by binding to the HMGCS1 promoter, thereby suppressing HMGCS1-mediated cholesterol biosynthesis and reducing CRC cell proliferation.","method":"ChIP-qPCR, luciferase reporter assay, KLF13 overexpression/knockdown with cholesterol measurement","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and luciferase reporter provide direct evidence of transcriptional regulation; single lab, multiple orthogonal methods","pmids":["32523679"],"is_preprint":false},{"year":2020,"finding":"HMGCS1 promotes gastric cancer progression through both metabolic (mevalonate pathway) and nonmetabolic functions: under serum deprivation, HMGCS1 translocates to the nucleus, directly binds to and activates Oct4 and SOX-2 promoters, and interacts with the ER stress transducer PERK to enhance the integrated stress response.","method":"ChIP assay, Co-IP, promoter binding assays, statin/dipyridamole pharmacological blockade, nuclear fractionation","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, fractionation) in single lab; nonmetabolic nuclear function supported by mevalonate pathway blockade experiments","pmids":["32349352"],"is_preprint":false},{"year":2019,"finding":"HMGCS1 enhances ERK phosphorylation (pERK) activity independently of the mevalonate pathway in colon cancer cells, and its suppression completely abolishes EGF-induced proliferation; SREBF2 is identified as a transcription factor regulating HMGCS1 expression.","method":"HMGCS1 knockdown, EGF stimulation, pERK measurement, SREBF2 transcription factor analysis","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined signaling readout (pERK), pharmacological dissection of MVA pathway independence, single lab","pmids":["31554653"],"is_preprint":false},{"year":2021,"finding":"GATA1 is identified as a direct upstream transcriptional regulator of HMGCS1, binding to the HMGCS1 promoter in AML cells; HMGCS1 protects mitochondria and ER from damage under ER stress and upregulates UPR downstream components, conferring chemotherapy resistance.","method":"Promoter binding assay, Tunicamycin ER stress treatment, mitochondrial analysis, UPR component measurement","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding and mechanistic ER/mitochondria functional assays; single lab, multiple assays","pmids":["33601148"],"is_preprint":false},{"year":2022,"finding":"Ursolic acid (UA) metabolite epoxy-modified UA irreversibly binds to the thiol of Cys-129 in HMGCS1, inhibiting its catalytic activity and reducing cholesterol biosynthesis precursor generation in vivo.","method":"Molecular docking, in-gel fluorescence scan, thermal shift assay, targeted metabolomics, fluorescence colocalization","journal":"Phytomedicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site residue (Cys-129) identified with irreversible covalent binding mechanism confirmed by multiple biochemical methods in single rigorous study; in vivo validation included","pmids":["35671633"],"is_preprint":false},{"year":2017,"finding":"Loss-of-function mutation of zebrafish hmgcs1 (encoding the first enzyme of the cholesterol synthesis pathway) causes craniofacial abnormalities via defects in cranial neural crest cell differentiation; isoprenoid synthesis (independent of cholesterol) was also found to have a novel role in facial development; Shh signaling was unaffected at early stages but gli1 expression was reduced at 4 dpf after morphological defects appeared.","method":"Zebrafish hmgcs1 loss-of-function mutation, pharmacological pathway inhibition, Shh pathway gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function combined with pharmacological dissection in zebrafish ortholog model; replicated across multiple conditions","pmids":["28686747"],"is_preprint":false},{"year":2019,"finding":"Mutation of zebrafish hmgcs1 decreases mature red blood cell numbers coinciding with reduced gata1a expression; isoprenoid synthesis (not cholesterol alone) is required for gata1a expression, establishing a novel role for HMGCS1-dependent isoprenoids as upstream regulators of GATA1 and RBC differentiation.","method":"Zebrafish hmgcs1 missense mutant analysis, RBC counting, gata1a expression, pharmacological inhibition of cholesterol/isoprenoid synthesis","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant combined with pharmacological epistasis in zebrafish; single lab with multiple orthogonal approaches","pmids":["30987969"],"is_preprint":false},{"year":2022,"finding":"HMGCS1 shows a compartmentalized distribution in nuclei, cytosol, and mitochondria of cervical cancer cells; cytosolic HMGCS1 regulates radiosensitivity via cholesterol metabolism, while mitochondrial HMGCS1 controls mitochondrial gene expression and sustains mitochondrial function.","method":"Subcellular fractionation, loss-of-function with radiosensitivity assay, mitochondrial gene expression analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation with functional consequence for each compartment; single lab","pmids":["36328117"],"is_preprint":false},{"year":2024,"finding":"CSN6 stabilizes HMGCS1 protein by antagonizing SPOP ubiquitin ligase-mediated degradation; stabilized HMGCS1 in turn activates YAP1 to promote hepatocellular carcinoma tumor growth.","method":"Co-IP, ubiquitination assay, HMGCS1 protein stability analysis, YAP1 activity measurement, orthotopic liver cancer models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay showing SPOP-HMGCS1 interaction with functional downstream YAP1 consequence; single lab, multiple orthogonal methods","pmids":["38308184"],"is_preprint":false},{"year":2022,"finding":"TET2 directly regulates HMGCS1 expression by catalyzing DNA demethylation on the HMGCS1 promoter region; TET2 deficiency leads to downregulation of HMGCS1 and the mevalonate pathway, sensitizing cells to statin-induced apoptosis via decreased geranylgeranyl diphosphate (GGPP) and impaired membrane localization of small GTPases.","method":"TET2 knockout, HMGCS1 promoter demethylation analysis, GGPP measurement, small GTPase membrane localization assay, HMGCS1 overexpression rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic mechanism (DNA demethylation of HMGCS1 promoter) with functional rescue; single lab, multiple orthogonal methods","pmids":["36348011"],"is_preprint":false},{"year":2022,"finding":"Metformin downregulates HMGCS1 expression through inhibition of the transcription factor NRF2 (nuclear factor E2-related factor 2), establishing NRF2 as an upstream transcriptional activator of HMGCS1.","method":"HMGCS1 expression analysis after metformin treatment, NRF2 inhibition/knockdown with reporter assays, in vitro and in vivo tumor models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcription factor-target relationship with pharmacological and genetic manipulation; single lab","pmids":["36356901"],"is_preprint":false},{"year":2021,"finding":"Gal-7 (galectin-7) directly interacts with HMGCS1 at phenylalanine 26 of HMGCS1; this interaction upregulates HMGCS1 expression in keratinocytes, increasing cellular cholesterol, and the two proteins engage in positive feedback regulation.","method":"Yeast two-hybrid, in vitro β-galactosidase assay, Biacore surface plasmon resonance, immunoprecipitation, F26 mutagenesis peptide inhibition","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — interaction site identified by mutagenesis (F26) with binding confirmed by multiple orthogonal biochemical methods (yeast two-hybrid, Biacore, Co-IP); single lab but rigorous","pmids":["34454908"],"is_preprint":false},{"year":2023,"finding":"Ligustilide (Lig) metabolic intermediate 6,7-epoxyligustilide irreversibly binds to Cys129 of HMGCS1 via covalent modification, inhibiting HMGCS1 catalytic activity and reducing cholesterol synthesis to ameliorate dyslipidemia.","method":"Chemical biological analysis, molecular docking, covalent binding assay targeting Cys129, in vivo hyperlipidemia model","journal":"Biomedicine & pharmacotherapy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site residue (Cys129) identified as covalent binding site confirmed by multiple chemical biology methods; corroborates Cys129 finding from UA study (PMID:35671633)","pmids":["37579692"],"is_preprint":false},{"year":2022,"finding":"KLF13 transcriptionally promotes HMGCS1 expression and cholesterol biosynthesis in hepatocellular carcinoma, as shown by dual-luciferase reporter assay and ChIP-seq confirming KLF13 binding to the HMGCS1 promoter, with KLF13 knockdown inhibiting cholesterol and HCC cell growth.","method":"Dual-luciferase reporter assay, ChIP-seq, KLF13 overexpression/knockdown, cholesterol measurement","journal":"Journal of clinical and translational hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and reporter assay confirm direct binding; single lab; contrasts with CRC paper (PMID:32523679) where KLF13 represses HMGCS1 — context-dependent regulation","pmids":["36381108"],"is_preprint":false},{"year":2024,"finding":"ACSS2 physically interacts with HMGCS1 (confirmed by Co-IP) in pancreatic neuroendocrine neoplasms; HMGCS1 can reverse the lipid metabolism reprogramming and PI3K/AKT/mTOR pathway effects caused by ACSS2 knockdown, placing HMGCS1 downstream of ACSS2 in this signaling axis.","method":"Co-immunoprecipitation, HMGCS1 overexpression rescue of ACSS2 knockdown, PI3K/AKT/mTOR pathway analysis, nude mouse xenografts","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms physical interaction; functional epistasis shown by rescue experiment; single lab","pmids":["38263056"],"is_preprint":false},{"year":2022,"finding":"STAT1 is a transcriptional activator of HMGCS1; miR-379-5p inhibits STAT1 expression thereby suppressing STAT1-driven HMGCS1 transcription and reducing free cholesterol accumulation in hepatocytes.","method":"Luciferase assay, mass spectrometry, STAT1 knockdown with HMGCS1 expression measurement, miR-379-5p overexpression in db/db mice","journal":"Molecular biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase and MS confirm STAT1-HMGCS1 transcriptional axis; validated in vivo; single lab","pmids":["35945406"],"is_preprint":false},{"year":2024,"finding":"HMGCS1 is subject to m6A RNA methylation by METTL3; YTHDF2 recognizes and degrades m6A-modified HMGCS1 mRNA, thereby reducing HMGCS1 protein levels and promoting ferroptosis in retinal ganglion cells under glutamate excitotoxicity.","method":"MeRIP-qPCR, siRNA knockdown of YTHDF2/HMGCS1, HMGCS1 lentiviral overexpression, ferroptosis markers, METTL3 inhibitor (STM2457), Western blot","journal":"International journal of surgery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A modification mechanism with writer (METTL3) and reader/degrader (YTHDF2) identified; multiple orthogonal methods; single lab","pmids":["40839015"],"is_preprint":false},{"year":2023,"finding":"ERRα directly interacts with HMGCS1 (confirmed by Co-IP) in endometrial cancer cells to regulate intracellular cholesterol metabolism and promote invadopodia formation, thereby enhancing cancer invasion and metastasis via the epithelial-mesenchymal transition pathway.","method":"Co-immunoprecipitation, ERRα/HMGCS1 loss-of-function and gain-of-function assays, cholesterol measurement, invasion assays, simvastatin treatment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirms physical interaction, functional assays link to invasion; single lab, multiple methods","pmids":["36835419"],"is_preprint":false},{"year":2025,"finding":"Biallelic missense variants in HMGCS1 cause rigid spine syndrome in humans; four tested variants (S447P, Q29L, M70T, C268S) show reduced HMGCS1 enzymatic activity and/or thermal stability while maintaining dimerization; mevalonic acid supplementation rescues the zebrafish mutant phenotype, establishing HMGCS1 as a disease gene acting through hypomorphic reduction of mevalonate pathway function.","method":"Recombinant protein enzymatic activity assay, thermal stability assay, dimerization assay, zebrafish rescue with HMGCS1 mRNA and mevalonic acid supplementation, exome/genome sequencing","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic and structural characterization of mutant proteins combined with in vivo zebrafish rescue; multiple independent families and multiple variants tested","pmids":["39531736"],"is_preprint":false},{"year":2024,"finding":"HMGCS1 knockdown in AML cells suppresses MAPK pathway activity, while HMGCS1 overexpression enhances it; MEK1 inhibitor U0126 offsets HMGCS1 overexpression effects, establishing that HMGCS1 promotes AML chemoresistance through the MAPK pathway.","method":"HMGCS1 knockout/overexpression, MAPK pathway phosphorylation analysis, MEK inhibitor epistasis, hymeglusin pharmacological inhibition","journal":"Blood science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with MEK inhibitor and genetic manipulation; single lab, multiple approaches","pmids":["38994525"],"is_preprint":false},{"year":2025,"finding":"Mitochondrial HMGCS1 associates with the D-loop region of mitochondrial DNA and is required for stable binding of core mitochondrial transcription machinery components (POLRMT, TFAM, TFB2M) to mtDNA, thereby regulating mitochondrial respiratory complex subunit transcription and mitochondrial respiratory capacity in cisplatin-resistant cervical cancer cells.","method":"Mitochondrial targeting construct, D-loop ChIP, Co-IP with POLRMT/TFAM/TFB2M, mitochondrial transcription and respiration assays, HMGCS1 inhibition/depletion with cisplatin sensitivity rescue","journal":"BMC molecular and cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical mechanism (mtDNA D-loop association, transcription factor co-IP) combined with compartment-specific targeting constructs and functional respiratory readout; single lab but multiple rigorous orthogonal methods","pmids":["41545954"],"is_preprint":false},{"year":2025,"finding":"HMGCS1 drives cholesterol-dependent plasma membrane repair after perforin-induced damage; cholesterol synthesized by HMGCS1 directly binds CHMP4B to enhance its plasma membrane localization, facilitating membrane repair and enabling tumor immune evasion; c-Jun transcriptionally upregulates HMGCS1 expression in response to oncogenic activation, cytokines, and hypoxia.","method":"Functional metabolic enzyme screen (111 enzymes), cholesterol-CHMP4B binding assay, HMGCS1 knockout with perforin/NK/CAR-T killing assays, c-Jun ChIP, PM repair assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional screen plus direct binding assay (cholesterol-CHMP4B) plus transcriptional mechanism (c-Jun ChIP) plus multiple immunotherapy models; rigorous multi-method study","pmids":["42248910"],"is_preprint":false},{"year":2025,"finding":"Activity-based chemical probes confirmed Hymeglusin as a selective covalent inhibitor of HMGCS1; inhibiting HMGCS1 causes proteome changes nearly identical to those caused by HMGCR inhibition or HMGCS1 degradation; simultaneous targeting of HMGCS1 and HMGCR suppresses growth of statin-resistant cancer cells and xenografts.","method":"Activity-based protein profiling, chemical proteomics, proteome-wide selectivity assay, xenograft tumor models, serum stability assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — chemical proteomics with activity-based probes provides mechanistic validation of inhibitor selectivity; preprint, single lab, but rigorous methods","pmids":["40631324"],"is_preprint":true},{"year":2023,"finding":"VIM-AS1 lncRNA promotes HMGCS1 mRNA stability through formation of a VIM-AS1/IGF2BP2/HMGCS1 RNA-protein complex, increasing HMGCS1 protein levels and promoting prostate cancer cell proliferation and enzalutamide resistance; HMGCS1 knockdown rescues VIM-AS1 overexpression-induced proliferation and resistance.","method":"RNA pulldown, RNA immunoprecipitation, RNA sequencing, HMGCS1 mRNA stability assay, rescue experiments","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown and RIP confirm complex; mRNA stability mechanism validated; rescue confirms functional relevance; single lab","pmids":["36734275"],"is_preprint":false},{"year":2025,"finding":"RPL6 directly binds the HMGCS1 mRNA 3'UTR (confirmed by RIP/binding assay), increasing HMGCS1 mRNA stability and protein expression; elevated HMGCS1-derived cholesterol inhibits ubiquitin-dependent HIF-1α degradation, activating HIF-1α signaling to promote HCC metastasis.","method":"HMGCS1 mRNA 3'UTR binding assay, mRNA stability analysis, cholesterol measurement, HIF-1α ubiquitination assay, in vitro and in vivo metastasis models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA binding and downstream HIF-1α stability mechanism; single lab, multiple methods","pmids":["40650669"],"is_preprint":false},{"year":2025,"finding":"In porcine Sertoli cells, HMGCS1 positively regulates dehydroepiandrosterone (DHEA) levels; melatonin treatment reduces HMGCS1 expression and estradiol levels, and direct HMGCS1 inhibition also reduces estradiol, establishing an HMGCS1-estradiol pathway in Sertoli cell steroidogenesis.","method":"Integrated transcriptomics/metabolomics, HMGCS1 inhibition with DHEA/estradiol measurement, RT-qPCR, Western blot","journal":"Theriogenology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative transcriptome/metabolome plus single direct inhibition experiment; single lab, non-human model","pmids":["40413863"],"is_preprint":false},{"year":2025,"finding":"Cerulenin dually targets and inhibits both FASN and HMGCS1 enzymatic activity; HMGCS1 inhibition by cerulenin disrupts the mevalonate pathway, leading to impaired selenocysteine tRNA maturation and subsequent suppression of GPX4 protein synthesis, enhancing tumor cell sensitivity to ferroptosis inducers.","method":"Enzymatic activity assay, mevalonate pathway metabolite analysis, selenocysteine tRNA and GPX4 synthesis measurement, xenograft tumor model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic inhibition assay combined with mechanistic downstream analysis of selenocysteine/GPX4 axis; single lab","pmids":["40848803"],"is_preprint":false}],"current_model":"HMGCS1 is the rate-limiting cytosolic enzyme catalyzing acetoacetyl-CoA + acetyl-CoA → HMG-CoA in the mevalonate/cholesterol biosynthesis pathway, with Cys129 as the catalytic active site susceptible to irreversible covalent inhibition; beyond its metabolic role, HMGCS1 is regulated at the transcriptional level by STAT3, NRF2, STAT1, SREBP2, KLF13, and c-Jun, at the post-translational level by SIRT1 deacetylation and SPOP ubiquitin ligase (antagonized by CSN6), and at the mRNA level by IGF2BP2-mediated stability and METTL3/YTHDF2-mediated m6A degradation; HMGCS1 localizes to cytosol, nucleus, and mitochondria with distinct compartment-specific functions — cytosolic for cholesterol synthesis, nuclear for direct promoter activation of pluripotency genes (Oct4/SOX2) and interaction with PERK, and mitochondrial for associating with the mtDNA D-loop to stabilize the core transcription machinery (POLRMT/TFAM/TFB2M) and regulate mitochondrial respiration; HMGCS1-derived cholesterol drives plasma membrane repair by directly binding CHMP4B to facilitate its membrane localization, enabling tumor immune evasion against perforin-mediated cytotoxic lymphocyte attack; and biallelic hypomorphic variants in HMGCS1 cause rigid spine syndrome in humans, rescued in zebrafish by mevalonic acid supplementation."},"narrative":{"mechanistic_narrative":"HMGCS1 is the cytosolic enzyme catalyzing the condensation step that generates HMG-CoA, committing acetyl units to the mevalonate/cholesterol biosynthesis pathway, and its activity governs cellular cholesterol and isoprenoid supply across development, metabolism, and cancer [PMID:35671633, PMID:39531736]. Catalysis depends on an active-site cysteine, Cys129, which is the target of irreversible covalent inhibition by epoxide-bearing natural-product metabolites of ursolic acid and ligustilide, and the enzyme is also blocked selectively by the covalent inhibitor hymeglusin [PMID:35671633, PMID:37579692, PMID:40631324]. Biallelic hypomorphic missense variants that reduce HMGCS1 enzymatic activity and thermal stability while sparing dimerization cause rigid spine syndrome in humans, with the zebrafish phenotype rescued by mevalonic acid supplementation, establishing HMGCS1 as a disease gene acting through partial loss of mevalonate pathway output [PMID:39531736]. Beyond canonical cytosolic cholesterol synthesis, HMGCS1 displays compartment-specific functions: it translocates to the nucleus to directly bind and activate the Oct4 and SOX2 promoters and engage the ER-stress transducer PERK, and a mitochondrial pool associates with the mtDNA D-loop to stabilize binding of the core transcription machinery POLRMT, TFAM, and TFB2M, sustaining respiratory subunit transcription and respiration [PMID:32349352, PMID:36328117, PMID:41545954]. HMGCS1-derived cholesterol mediates plasma-membrane repair by directly binding CHMP4B to promote its membrane localization, enabling tumor cells to evade perforin-mediated cytotoxic lymphocyte killing [PMID:42248910]. HMGCS1 expression is tightly controlled: transcriptionally activated by SREBF2, NRF2, STAT1, GATA1, ERRα, and c-Jun and repressed or promoted in a context-dependent manner by KLF13, with TET2-driven promoter demethylation as an additional input; its mRNA is stabilized by IGF2BP2- and RPL6-containing complexes and degraded via METTL3/YTHDF2 m6A turnover; and its protein is deacetylated by SIRT1 and stabilized when CSN6 antagonizes SPOP-mediated ubiquitination [PMID:21701047, PMID:32523679, PMID:31554653, PMID:38308184, PMID:36348011, PMID:36356901, PMID:36381108, PMID:35945406, PMID:40839015, PMID:42248910, PMID:36734275, PMID:40650669]. Through these inputs HMGCS1 sustains mevalonate-dependent prenylation, ERK/MAPK signaling, and downstream oncogenic effectors such as YAP1 and HIF-1α to drive proliferation, invasion, and therapy resistance in multiple cancers [PMID:31554653, PMID:38308184, PMID:36348011, PMID:38994525, PMID:40650669].","teleology":[{"year":2011,"claim":"Established that HMGCS1 is not only a metabolic enzyme but a post-translationally regulated protein, identifying it as a cytoplasmic SIRT1 deacetylation substrate parallel to the mitochondrial HMGCS2/SIRT3 pair.","evidence":"deacetylation assay with substrate-homology analysis","pmids":["21701047"],"confidence":"Medium","gaps":["Functional consequence of HMGCS1 acetylation/deacetylation on enzyme activity not defined","Specific acetylated lysines not mapped"]},{"year":2017,"claim":"Linked HMGCS1 mevalonate output to organismal phenotype, showing its loss disrupts cranial neural crest differentiation via isoprenoid (not solely cholesterol) synthesis, while also tying it to cancer cell viability through autocrine/paracrine pathway activity.","evidence":"zebrafish hmgcs1 loss-of-function with pharmacological dissection; shRNA knockdown and overexpression in prostate cancer cells","pmids":["28686747","29163687"],"confidence":"Medium","gaps":["Molecular targets of isoprenoid signaling in neural crest unresolved","Shh pathway changes appeared only after morphological defects, leaving causality unclear"]},{"year":2019,"claim":"Revealed a mevalonate-independent signaling role and identified the first transcriptional regulators, showing HMGCS1 enhances ERK phosphorylation and EGF-driven proliferation while SREBF2 and GATA1-dependent isoprenoids feed into HMGCS1/GATA1-controlled erythroid differentiation.","evidence":"knockdown with pERK readout and pathway-independence pharmacology; zebrafish missense mutant with gata1a expression and isoprenoid epistasis","pmids":["31554653","30987969"],"confidence":"Medium","gaps":["Mechanism by which HMGCS1 enhances ERK independently of catalysis unknown","Direct molecular link between isoprenoids and gata1a not identified"]},{"year":2020,"claim":"Defined a moonlighting nuclear function and context-dependent transcriptional control, demonstrating nuclear HMGCS1 directly activates pluripotency promoters and binds PERK, while KLF13 represses HMGCS1 to limit cholesterol synthesis and proliferation.","evidence":"ChIP, Co-IP, nuclear fractionation, and pathway-blockade in gastric cancer; ChIP-qPCR and luciferase reporter with KLF13 manipulation in CRC","pmids":["32349352","32523679"],"confidence":"Medium","gaps":["Signal/mechanism driving HMGCS1 nuclear translocation unresolved","Whether nuclear DNA binding is direct or via cofactors not established"]},{"year":2021,"claim":"Expanded the regulatory network and stress-protective role, identifying GATA1 as a direct activator and showing HMGCS1 protects mitochondria/ER under stress and engages in Gal-7 positive feedback via a defined interaction at Phe26.","evidence":"promoter binding and ER-stress/UPR assays in AML; yeast two-hybrid, Biacore SPR, Co-IP, and F26 mutagenesis in keratinocytes","pmids":["33601148","34454908"],"confidence":"Medium","gaps":["Whether Gal-7 binding alters HMGCS1 catalysis directly is not shown","Mechanism of ER/mitochondrial protection beyond UPR upregulation not defined"]},{"year":2022,"claim":"Pinpointed the catalytic active site and mapped multilayer expression control, showing Cys129 is the irreversibly inhibited residue and that NRF2, STAT1, TET2 demethylation, and KLF13 all converge on HMGCS1 transcription, with distinct cytosolic versus mitochondrial functional compartments emerging.","evidence":"covalent-binding chemical biology (ursolic acid metabolite, Cys129); transcription factor reporter/knockdown studies; TET2 promoter demethylation with GGPP and GTPase localization rescue; subcellular fractionation with compartment-specific functional assays","pmids":["35671633","36356901","35945406","36348011","32523679","36328117","36381108"],"confidence":"High","gaps":["Opposing KLF13 effects in CRC versus HCC indicate unresolved context dependence","Mechanism targeting HMGCS1 to mitochondria not defined at this stage"]},{"year":2023,"claim":"Extended HMGCS1 into invasion programs and mRNA-stability control, showing ERRα physically interacts with HMGCS1 to promote invadopodia/EMT and that a second covalent ligand (ligustilide metabolite) confirms Cys129, while VIM-AS1/IGF2BP2 stabilizes HMGCS1 mRNA.","evidence":"Co-IP and invasion assays with ERRα; covalent Cys129 binding assay; RNA pulldown/RIP and mRNA-stability/rescue experiments","pmids":["36835419","37579692","36734275"],"confidence":"Medium","gaps":["Whether ERRα binding affects HMGCS1 catalysis or localization unclear","Direct versus scaffolded IGF2BP2 binding to HMGCS1 transcript not fully resolved"]},{"year":2024,"claim":"Consolidated post-translational and signaling axes, showing CSN6 stabilizes HMGCS1 against SPOP-mediated degradation to activate YAP1, that ACSS2 physically partners with HMGCS1 upstream of PI3K/AKT/mTOR, that m6A (METTL3/YTHDF2) controls HMGCS1 mRNA fate, and that HMGCS1 drives AML chemoresistance through MAPK.","evidence":"Co-IP, ubiquitination, and YAP1 assays; Co-IP and rescue epistasis with ACSS2; MeRIP-qPCR with writer/reader manipulation; MEK-inhibitor epistasis with genetic manipulation","pmids":["38308184","38263056","40839015","38994525"],"confidence":"Medium","gaps":["Whether ACSS2-HMGCS1 binding is metabolic channeling or signaling scaffolding not resolved","How HMGCS1 mechanistically activates YAP1 and MAPK not fully defined"]},{"year":2025,"claim":"Delivered the strongest mechanistic and disease-level evidence: a mitochondrial HMGCS1 pool stabilizes the mtDNA transcription machinery at the D-loop; cholesterol made by HMGCS1 directly binds CHMP4B to drive membrane repair and immune evasion; and biallelic hypomorphic variants cause rigid spine syndrome rescued by mevalonic acid.","evidence":"D-loop ChIP and Co-IP with POLRMT/TFAM/TFB2M plus respiration assays; functional enzyme screen with cholesterol-CHMP4B binding and perforin/NK/CAR-T killing assays plus c-Jun ChIP; recombinant mutant enzymology/stability with zebrafish mevalonic-acid rescue and exome sequencing","pmids":["41545954","42248910","39531736"],"confidence":"High","gaps":["How HMGCS1 is imported into mitochondria and nucleus is unresolved","Whether mitochondrial/nuclear functions require catalytic activity not fully separated from metabolic effects"]},{"year":2025,"claim":"Refined therapeutic targeting and downstream metabolic consequences, validating hymeglusin as a selective covalent HMGCS1 inhibitor whose effects mirror HMGCR loss, linking HMGCS1 to HIF-1α stabilization, GPX4/selenocysteine-tRNA-dependent ferroptosis, and steroidogenesis.","evidence":"activity-based protein profiling and chemical proteomics (preprint); RPL6 3'UTR binding with HIF-1α ubiquitination assays; cerulenin enzymatic inhibition with selenocysteine-tRNA/GPX4 analysis; transcriptomics/metabolomics with HMGCS1 inhibition in Sertoli cells","pmids":["40631324","40650669","40848803","40413863"],"confidence":"Medium","gaps":["Sertoli-cell steroidogenesis link is correlative and from a non-human model","Selectivity of cerulenin between FASN and HMGCS1 in cells not fully separated"]},{"year":null,"claim":"The signals and import machinery that direct HMGCS1 to the nucleus and mitochondria, and whether its moonlighting transcriptional and membrane-repair roles depend on catalysis versus protein scaffolding, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of compartment-specific HMGCS1 complexes","Catalysis-dependent versus -independent moonlighting functions not cleanly separated","Mechanism of regulated subcellular targeting unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[6,14,20,24]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[6,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,22]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9,22]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,14,20,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression 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HMGCS1 in the cytoplasm, establishing HMGCS1 as a substrate for the cytoplasmic deacetylase SIRT1 (analogous to the SIRT3/HMGCS2 pair in mitochondria).\",\n      \"method\": \"Deacetylation assay; evolutionary/substrate homology analysis\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, reported as direct deacetylation but abstract is brief and lacks full methodological detail; supported by parallel AceCS1/2 and HMGCS2/SIRT3 paradigm\",\n      \"pmids\": [\"21701047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of HMGCS1 by shRNA significantly reduces prostate cancer cell viability, and exogenous overexpression of HMGCS1 in prostate cancer or stromal cells stimulates cancer cell growth, demonstrating a functional role via autocrine/paracrine mevalonate pathway activity.\",\n      \"method\": \"shRNA knockdown, overexpression, cell viability assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype, single lab, two complementary approaches\",\n      \"pmids\": [\"29163687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KLF13 transcriptionally inhibits HMGCS1 expression by binding to the HMGCS1 promoter, thereby suppressing HMGCS1-mediated cholesterol biosynthesis and reducing CRC cell proliferation.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, KLF13 overexpression/knockdown with cholesterol measurement\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and luciferase reporter provide direct evidence of transcriptional regulation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32523679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HMGCS1 promotes gastric cancer progression through both metabolic (mevalonate pathway) and nonmetabolic functions: under serum deprivation, HMGCS1 translocates to the nucleus, directly binds to and activates Oct4 and SOX-2 promoters, and interacts with the ER stress transducer PERK to enhance the integrated stress response.\",\n      \"method\": \"ChIP assay, Co-IP, promoter binding assays, statin/dipyridamole pharmacological blockade, nuclear fractionation\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, fractionation) in single lab; nonmetabolic nuclear function supported by mevalonate pathway blockade experiments\",\n      \"pmids\": [\"32349352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HMGCS1 enhances ERK phosphorylation (pERK) activity independently of the mevalonate pathway in colon cancer cells, and its suppression completely abolishes EGF-induced proliferation; SREBF2 is identified as a transcription factor regulating HMGCS1 expression.\",\n      \"method\": \"HMGCS1 knockdown, EGF stimulation, pERK measurement, SREBF2 transcription factor analysis\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined signaling readout (pERK), pharmacological dissection of MVA pathway independence, single lab\",\n      \"pmids\": [\"31554653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GATA1 is identified as a direct upstream transcriptional regulator of HMGCS1, binding to the HMGCS1 promoter in AML cells; HMGCS1 protects mitochondria and ER from damage under ER stress and upregulates UPR downstream components, conferring chemotherapy resistance.\",\n      \"method\": \"Promoter binding assay, Tunicamycin ER stress treatment, mitochondrial analysis, UPR component measurement\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding and mechanistic ER/mitochondria functional assays; single lab, multiple assays\",\n      \"pmids\": [\"33601148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ursolic acid (UA) metabolite epoxy-modified UA irreversibly binds to the thiol of Cys-129 in HMGCS1, inhibiting its catalytic activity and reducing cholesterol biosynthesis precursor generation in vivo.\",\n      \"method\": \"Molecular docking, in-gel fluorescence scan, thermal shift assay, targeted metabolomics, fluorescence colocalization\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site residue (Cys-129) identified with irreversible covalent binding mechanism confirmed by multiple biochemical methods in single rigorous study; in vivo validation included\",\n      \"pmids\": [\"35671633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss-of-function mutation of zebrafish hmgcs1 (encoding the first enzyme of the cholesterol synthesis pathway) causes craniofacial abnormalities via defects in cranial neural crest cell differentiation; isoprenoid synthesis (independent of cholesterol) was also found to have a novel role in facial development; Shh signaling was unaffected at early stages but gli1 expression was reduced at 4 dpf after morphological defects appeared.\",\n      \"method\": \"Zebrafish hmgcs1 loss-of-function mutation, pharmacological pathway inhibition, Shh pathway gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function combined with pharmacological dissection in zebrafish ortholog model; replicated across multiple conditions\",\n      \"pmids\": [\"28686747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mutation of zebrafish hmgcs1 decreases mature red blood cell numbers coinciding with reduced gata1a expression; isoprenoid synthesis (not cholesterol alone) is required for gata1a expression, establishing a novel role for HMGCS1-dependent isoprenoids as upstream regulators of GATA1 and RBC differentiation.\",\n      \"method\": \"Zebrafish hmgcs1 missense mutant analysis, RBC counting, gata1a expression, pharmacological inhibition of cholesterol/isoprenoid synthesis\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant combined with pharmacological epistasis in zebrafish; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"30987969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMGCS1 shows a compartmentalized distribution in nuclei, cytosol, and mitochondria of cervical cancer cells; cytosolic HMGCS1 regulates radiosensitivity via cholesterol metabolism, while mitochondrial HMGCS1 controls mitochondrial gene expression and sustains mitochondrial function.\",\n      \"method\": \"Subcellular fractionation, loss-of-function with radiosensitivity assay, mitochondrial gene expression analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation with functional consequence for each compartment; single lab\",\n      \"pmids\": [\"36328117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CSN6 stabilizes HMGCS1 protein by antagonizing SPOP ubiquitin ligase-mediated degradation; stabilized HMGCS1 in turn activates YAP1 to promote hepatocellular carcinoma tumor growth.\",\n      \"method\": \"Co-IP, ubiquitination assay, HMGCS1 protein stability analysis, YAP1 activity measurement, orthotopic liver cancer models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay showing SPOP-HMGCS1 interaction with functional downstream YAP1 consequence; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38308184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TET2 directly regulates HMGCS1 expression by catalyzing DNA demethylation on the HMGCS1 promoter region; TET2 deficiency leads to downregulation of HMGCS1 and the mevalonate pathway, sensitizing cells to statin-induced apoptosis via decreased geranylgeranyl diphosphate (GGPP) and impaired membrane localization of small GTPases.\",\n      \"method\": \"TET2 knockout, HMGCS1 promoter demethylation analysis, GGPP measurement, small GTPase membrane localization assay, HMGCS1 overexpression rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic mechanism (DNA demethylation of HMGCS1 promoter) with functional rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36348011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Metformin downregulates HMGCS1 expression through inhibition of the transcription factor NRF2 (nuclear factor E2-related factor 2), establishing NRF2 as an upstream transcriptional activator of HMGCS1.\",\n      \"method\": \"HMGCS1 expression analysis after metformin treatment, NRF2 inhibition/knockdown with reporter assays, in vitro and in vivo tumor models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcription factor-target relationship with pharmacological and genetic manipulation; single lab\",\n      \"pmids\": [\"36356901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Gal-7 (galectin-7) directly interacts with HMGCS1 at phenylalanine 26 of HMGCS1; this interaction upregulates HMGCS1 expression in keratinocytes, increasing cellular cholesterol, and the two proteins engage in positive feedback regulation.\",\n      \"method\": \"Yeast two-hybrid, in vitro β-galactosidase assay, Biacore surface plasmon resonance, immunoprecipitation, F26 mutagenesis peptide inhibition\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — interaction site identified by mutagenesis (F26) with binding confirmed by multiple orthogonal biochemical methods (yeast two-hybrid, Biacore, Co-IP); single lab but rigorous\",\n      \"pmids\": [\"34454908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ligustilide (Lig) metabolic intermediate 6,7-epoxyligustilide irreversibly binds to Cys129 of HMGCS1 via covalent modification, inhibiting HMGCS1 catalytic activity and reducing cholesterol synthesis to ameliorate dyslipidemia.\",\n      \"method\": \"Chemical biological analysis, molecular docking, covalent binding assay targeting Cys129, in vivo hyperlipidemia model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site residue (Cys129) identified as covalent binding site confirmed by multiple chemical biology methods; corroborates Cys129 finding from UA study (PMID:35671633)\",\n      \"pmids\": [\"37579692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KLF13 transcriptionally promotes HMGCS1 expression and cholesterol biosynthesis in hepatocellular carcinoma, as shown by dual-luciferase reporter assay and ChIP-seq confirming KLF13 binding to the HMGCS1 promoter, with KLF13 knockdown inhibiting cholesterol and HCC cell growth.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP-seq, KLF13 overexpression/knockdown, cholesterol measurement\",\n      \"journal\": \"Journal of clinical and translational hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and reporter assay confirm direct binding; single lab; contrasts with CRC paper (PMID:32523679) where KLF13 represses HMGCS1 — context-dependent regulation\",\n      \"pmids\": [\"36381108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 physically interacts with HMGCS1 (confirmed by Co-IP) in pancreatic neuroendocrine neoplasms; HMGCS1 can reverse the lipid metabolism reprogramming and PI3K/AKT/mTOR pathway effects caused by ACSS2 knockdown, placing HMGCS1 downstream of ACSS2 in this signaling axis.\",\n      \"method\": \"Co-immunoprecipitation, HMGCS1 overexpression rescue of ACSS2 knockdown, PI3K/AKT/mTOR pathway analysis, nude mouse xenografts\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms physical interaction; functional epistasis shown by rescue experiment; single lab\",\n      \"pmids\": [\"38263056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STAT1 is a transcriptional activator of HMGCS1; miR-379-5p inhibits STAT1 expression thereby suppressing STAT1-driven HMGCS1 transcription and reducing free cholesterol accumulation in hepatocytes.\",\n      \"method\": \"Luciferase assay, mass spectrometry, STAT1 knockdown with HMGCS1 expression measurement, miR-379-5p overexpression in db/db mice\",\n      \"journal\": \"Molecular biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase and MS confirm STAT1-HMGCS1 transcriptional axis; validated in vivo; single lab\",\n      \"pmids\": [\"35945406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMGCS1 is subject to m6A RNA methylation by METTL3; YTHDF2 recognizes and degrades m6A-modified HMGCS1 mRNA, thereby reducing HMGCS1 protein levels and promoting ferroptosis in retinal ganglion cells under glutamate excitotoxicity.\",\n      \"method\": \"MeRIP-qPCR, siRNA knockdown of YTHDF2/HMGCS1, HMGCS1 lentiviral overexpression, ferroptosis markers, METTL3 inhibitor (STM2457), Western blot\",\n      \"journal\": \"International journal of surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A modification mechanism with writer (METTL3) and reader/degrader (YTHDF2) identified; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"40839015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERRα directly interacts with HMGCS1 (confirmed by Co-IP) in endometrial cancer cells to regulate intracellular cholesterol metabolism and promote invadopodia formation, thereby enhancing cancer invasion and metastasis via the epithelial-mesenchymal transition pathway.\",\n      \"method\": \"Co-immunoprecipitation, ERRα/HMGCS1 loss-of-function and gain-of-function assays, cholesterol measurement, invasion assays, simvastatin treatment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirms physical interaction, functional assays link to invasion; single lab, multiple methods\",\n      \"pmids\": [\"36835419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic missense variants in HMGCS1 cause rigid spine syndrome in humans; four tested variants (S447P, Q29L, M70T, C268S) show reduced HMGCS1 enzymatic activity and/or thermal stability while maintaining dimerization; mevalonic acid supplementation rescues the zebrafish mutant phenotype, establishing HMGCS1 as a disease gene acting through hypomorphic reduction of mevalonate pathway function.\",\n      \"method\": \"Recombinant protein enzymatic activity assay, thermal stability assay, dimerization assay, zebrafish rescue with HMGCS1 mRNA and mevalonic acid supplementation, exome/genome sequencing\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic and structural characterization of mutant proteins combined with in vivo zebrafish rescue; multiple independent families and multiple variants tested\",\n      \"pmids\": [\"39531736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMGCS1 knockdown in AML cells suppresses MAPK pathway activity, while HMGCS1 overexpression enhances it; MEK1 inhibitor U0126 offsets HMGCS1 overexpression effects, establishing that HMGCS1 promotes AML chemoresistance through the MAPK pathway.\",\n      \"method\": \"HMGCS1 knockout/overexpression, MAPK pathway phosphorylation analysis, MEK inhibitor epistasis, hymeglusin pharmacological inhibition\",\n      \"journal\": \"Blood science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with MEK inhibitor and genetic manipulation; single lab, multiple approaches\",\n      \"pmids\": [\"38994525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mitochondrial HMGCS1 associates with the D-loop region of mitochondrial DNA and is required for stable binding of core mitochondrial transcription machinery components (POLRMT, TFAM, TFB2M) to mtDNA, thereby regulating mitochondrial respiratory complex subunit transcription and mitochondrial respiratory capacity in cisplatin-resistant cervical cancer cells.\",\n      \"method\": \"Mitochondrial targeting construct, D-loop ChIP, Co-IP with POLRMT/TFAM/TFB2M, mitochondrial transcription and respiration assays, HMGCS1 inhibition/depletion with cisplatin sensitivity rescue\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical mechanism (mtDNA D-loop association, transcription factor co-IP) combined with compartment-specific targeting constructs and functional respiratory readout; single lab but multiple rigorous orthogonal methods\",\n      \"pmids\": [\"41545954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMGCS1 drives cholesterol-dependent plasma membrane repair after perforin-induced damage; cholesterol synthesized by HMGCS1 directly binds CHMP4B to enhance its plasma membrane localization, facilitating membrane repair and enabling tumor immune evasion; c-Jun transcriptionally upregulates HMGCS1 expression in response to oncogenic activation, cytokines, and hypoxia.\",\n      \"method\": \"Functional metabolic enzyme screen (111 enzymes), cholesterol-CHMP4B binding assay, HMGCS1 knockout with perforin/NK/CAR-T killing assays, c-Jun ChIP, PM repair assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional screen plus direct binding assay (cholesterol-CHMP4B) plus transcriptional mechanism (c-Jun ChIP) plus multiple immunotherapy models; rigorous multi-method study\",\n      \"pmids\": [\"42248910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Activity-based chemical probes confirmed Hymeglusin as a selective covalent inhibitor of HMGCS1; inhibiting HMGCS1 causes proteome changes nearly identical to those caused by HMGCR inhibition or HMGCS1 degradation; simultaneous targeting of HMGCS1 and HMGCR suppresses growth of statin-resistant cancer cells and xenografts.\",\n      \"method\": \"Activity-based protein profiling, chemical proteomics, proteome-wide selectivity assay, xenograft tumor models, serum stability assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical proteomics with activity-based probes provides mechanistic validation of inhibitor selectivity; preprint, single lab, but rigorous methods\",\n      \"pmids\": [\"40631324\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VIM-AS1 lncRNA promotes HMGCS1 mRNA stability through formation of a VIM-AS1/IGF2BP2/HMGCS1 RNA-protein complex, increasing HMGCS1 protein levels and promoting prostate cancer cell proliferation and enzalutamide resistance; HMGCS1 knockdown rescues VIM-AS1 overexpression-induced proliferation and resistance.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, RNA sequencing, HMGCS1 mRNA stability assay, rescue experiments\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown and RIP confirm complex; mRNA stability mechanism validated; rescue confirms functional relevance; single lab\",\n      \"pmids\": [\"36734275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPL6 directly binds the HMGCS1 mRNA 3'UTR (confirmed by RIP/binding assay), increasing HMGCS1 mRNA stability and protein expression; elevated HMGCS1-derived cholesterol inhibits ubiquitin-dependent HIF-1α degradation, activating HIF-1α signaling to promote HCC metastasis.\",\n      \"method\": \"HMGCS1 mRNA 3'UTR binding assay, mRNA stability analysis, cholesterol measurement, HIF-1α ubiquitination assay, in vitro and in vivo metastasis models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA binding and downstream HIF-1α stability mechanism; single lab, multiple methods\",\n      \"pmids\": [\"40650669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In porcine Sertoli cells, HMGCS1 positively regulates dehydroepiandrosterone (DHEA) levels; melatonin treatment reduces HMGCS1 expression and estradiol levels, and direct HMGCS1 inhibition also reduces estradiol, establishing an HMGCS1-estradiol pathway in Sertoli cell steroidogenesis.\",\n      \"method\": \"Integrated transcriptomics/metabolomics, HMGCS1 inhibition with DHEA/estradiol measurement, RT-qPCR, Western blot\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative transcriptome/metabolome plus single direct inhibition experiment; single lab, non-human model\",\n      \"pmids\": [\"40413863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cerulenin dually targets and inhibits both FASN and HMGCS1 enzymatic activity; HMGCS1 inhibition by cerulenin disrupts the mevalonate pathway, leading to impaired selenocysteine tRNA maturation and subsequent suppression of GPX4 protein synthesis, enhancing tumor cell sensitivity to ferroptosis inducers.\",\n      \"method\": \"Enzymatic activity assay, mevalonate pathway metabolite analysis, selenocysteine tRNA and GPX4 synthesis measurement, xenograft tumor model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic inhibition assay combined with mechanistic downstream analysis of selenocysteine/GPX4 axis; single lab\",\n      \"pmids\": [\"40848803\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMGCS1 is the rate-limiting cytosolic enzyme catalyzing acetoacetyl-CoA + acetyl-CoA → HMG-CoA in the mevalonate/cholesterol biosynthesis pathway, with Cys129 as the catalytic active site susceptible to irreversible covalent inhibition; beyond its metabolic role, HMGCS1 is regulated at the transcriptional level by STAT3, NRF2, STAT1, SREBP2, KLF13, and c-Jun, at the post-translational level by SIRT1 deacetylation and SPOP ubiquitin ligase (antagonized by CSN6), and at the mRNA level by IGF2BP2-mediated stability and METTL3/YTHDF2-mediated m6A degradation; HMGCS1 localizes to cytosol, nucleus, and mitochondria with distinct compartment-specific functions — cytosolic for cholesterol synthesis, nuclear for direct promoter activation of pluripotency genes (Oct4/SOX2) and interaction with PERK, and mitochondrial for associating with the mtDNA D-loop to stabilize the core transcription machinery (POLRMT/TFAM/TFB2M) and regulate mitochondrial respiration; HMGCS1-derived cholesterol drives plasma membrane repair by directly binding CHMP4B to facilitate its membrane localization, enabling tumor immune evasion against perforin-mediated cytotoxic lymphocyte attack; and biallelic hypomorphic variants in HMGCS1 cause rigid spine syndrome in humans, rescued in zebrafish by mevalonic acid supplementation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HMGCS1 is the cytosolic enzyme catalyzing the condensation step that generates HMG-CoA, committing acetyl units to the mevalonate/cholesterol biosynthesis pathway, and its activity governs cellular cholesterol and isoprenoid supply across development, metabolism, and cancer [#6, #20]. Catalysis depends on an active-site cysteine, Cys129, which is the target of irreversible covalent inhibition by epoxide-bearing natural-product metabolites of ursolic acid and ligustilide, and the enzyme is also blocked selectively by the covalent inhibitor hymeglusin [#6, #14, #24]. Biallelic hypomorphic missense variants that reduce HMGCS1 enzymatic activity and thermal stability while sparing dimerization cause rigid spine syndrome in humans, with the zebrafish phenotype rescued by mevalonic acid supplementation, establishing HMGCS1 as a disease gene acting through partial loss of mevalonate pathway output [#20]. Beyond canonical cytosolic cholesterol synthesis, HMGCS1 displays compartment-specific functions: it translocates to the nucleus to directly bind and activate the Oct4 and SOX2 promoters and engage the ER-stress transducer PERK, and a mitochondrial pool associates with the mtDNA D-loop to stabilize binding of the core transcription machinery POLRMT, TFAM, and TFB2M, sustaining respiratory subunit transcription and respiration [#3, #9, #22]. HMGCS1-derived cholesterol mediates plasma-membrane repair by directly binding CHMP4B to promote its membrane localization, enabling tumor cells to evade perforin-mediated cytotoxic lymphocyte killing [#23]. HMGCS1 expression is tightly controlled: transcriptionally activated by SREBF2, NRF2, STAT1, GATA1, ERRα, and c-Jun and repressed or promoted in a context-dependent manner by KLF13, with TET2-driven promoter demethylation as an additional input; its mRNA is stabilized by IGF2BP2- and RPL6-containing complexes and degraded via METTL3/YTHDF2 m6A turnover; and its protein is deacetylated by SIRT1 and stabilized when CSN6 antagonizes SPOP-mediated ubiquitination [#0, #2, #4, #10, #11, #12, #15, #17, #18, #23, #25, #26]. Through these inputs HMGCS1 sustains mevalonate-dependent prenylation, ERK/MAPK signaling, and downstream oncogenic effectors such as YAP1 and HIF-1α to drive proliferation, invasion, and therapy resistance in multiple cancers [#4, #10, #11, #21, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that HMGCS1 is not only a metabolic enzyme but a post-translationally regulated protein, identifying it as a cytoplasmic SIRT1 deacetylation substrate parallel to the mitochondrial HMGCS2/SIRT3 pair.\",\n      \"evidence\": \"deacetylation assay with substrate-homology analysis\",\n      \"pmids\": [\"21701047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of HMGCS1 acetylation/deacetylation on enzyme activity not defined\", \"Specific acetylated lysines not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked HMGCS1 mevalonate output to organismal phenotype, showing its loss disrupts cranial neural crest differentiation via isoprenoid (not solely cholesterol) synthesis, while also tying it to cancer cell viability through autocrine/paracrine pathway activity.\",\n      \"evidence\": \"zebrafish hmgcs1 loss-of-function with pharmacological dissection; shRNA knockdown and overexpression in prostate cancer cells\",\n      \"pmids\": [\"28686747\", \"29163687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets of isoprenoid signaling in neural crest unresolved\", \"Shh pathway changes appeared only after morphological defects, leaving causality unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a mevalonate-independent signaling role and identified the first transcriptional regulators, showing HMGCS1 enhances ERK phosphorylation and EGF-driven proliferation while SREBF2 and GATA1-dependent isoprenoids feed into HMGCS1/GATA1-controlled erythroid differentiation.\",\n      \"evidence\": \"knockdown with pERK readout and pathway-independence pharmacology; zebrafish missense mutant with gata1a expression and isoprenoid epistasis\",\n      \"pmids\": [\"31554653\", \"30987969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which HMGCS1 enhances ERK independently of catalysis unknown\", \"Direct molecular link between isoprenoids and gata1a not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a moonlighting nuclear function and context-dependent transcriptional control, demonstrating nuclear HMGCS1 directly activates pluripotency promoters and binds PERK, while KLF13 represses HMGCS1 to limit cholesterol synthesis and proliferation.\",\n      \"evidence\": \"ChIP, Co-IP, nuclear fractionation, and pathway-blockade in gastric cancer; ChIP-qPCR and luciferase reporter with KLF13 manipulation in CRC\",\n      \"pmids\": [\"32349352\", \"32523679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal/mechanism driving HMGCS1 nuclear translocation unresolved\", \"Whether nuclear DNA binding is direct or via cofactors not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the regulatory network and stress-protective role, identifying GATA1 as a direct activator and showing HMGCS1 protects mitochondria/ER under stress and engages in Gal-7 positive feedback via a defined interaction at Phe26.\",\n      \"evidence\": \"promoter binding and ER-stress/UPR assays in AML; yeast two-hybrid, Biacore SPR, Co-IP, and F26 mutagenesis in keratinocytes\",\n      \"pmids\": [\"33601148\", \"34454908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Gal-7 binding alters HMGCS1 catalysis directly is not shown\", \"Mechanism of ER/mitochondrial protection beyond UPR upregulation not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pinpointed the catalytic active site and mapped multilayer expression control, showing Cys129 is the irreversibly inhibited residue and that NRF2, STAT1, TET2 demethylation, and KLF13 all converge on HMGCS1 transcription, with distinct cytosolic versus mitochondrial functional compartments emerging.\",\n      \"evidence\": \"covalent-binding chemical biology (ursolic acid metabolite, Cys129); transcription factor reporter/knockdown studies; TET2 promoter demethylation with GGPP and GTPase localization rescue; subcellular fractionation with compartment-specific functional assays\",\n      \"pmids\": [\"35671633\", \"36356901\", \"35945406\", \"36348011\", \"32523679\", \"36328117\", \"36381108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Opposing KLF13 effects in CRC versus HCC indicate unresolved context dependence\", \"Mechanism targeting HMGCS1 to mitochondria not defined at this stage\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended HMGCS1 into invasion programs and mRNA-stability control, showing ERRα physically interacts with HMGCS1 to promote invadopodia/EMT and that a second covalent ligand (ligustilide metabolite) confirms Cys129, while VIM-AS1/IGF2BP2 stabilizes HMGCS1 mRNA.\",\n      \"evidence\": \"Co-IP and invasion assays with ERRα; covalent Cys129 binding assay; RNA pulldown/RIP and mRNA-stability/rescue experiments\",\n      \"pmids\": [\"36835419\", \"37579692\", \"36734275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ERRα binding affects HMGCS1 catalysis or localization unclear\", \"Direct versus scaffolded IGF2BP2 binding to HMGCS1 transcript not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated post-translational and signaling axes, showing CSN6 stabilizes HMGCS1 against SPOP-mediated degradation to activate YAP1, that ACSS2 physically partners with HMGCS1 upstream of PI3K/AKT/mTOR, that m6A (METTL3/YTHDF2) controls HMGCS1 mRNA fate, and that HMGCS1 drives AML chemoresistance through MAPK.\",\n      \"evidence\": \"Co-IP, ubiquitination, and YAP1 assays; Co-IP and rescue epistasis with ACSS2; MeRIP-qPCR with writer/reader manipulation; MEK-inhibitor epistasis with genetic manipulation\",\n      \"pmids\": [\"38308184\", \"38263056\", \"40839015\", \"38994525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ACSS2-HMGCS1 binding is metabolic channeling or signaling scaffolding not resolved\", \"How HMGCS1 mechanistically activates YAP1 and MAPK not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Delivered the strongest mechanistic and disease-level evidence: a mitochondrial HMGCS1 pool stabilizes the mtDNA transcription machinery at the D-loop; cholesterol made by HMGCS1 directly binds CHMP4B to drive membrane repair and immune evasion; and biallelic hypomorphic variants cause rigid spine syndrome rescued by mevalonic acid.\",\n      \"evidence\": \"D-loop ChIP and Co-IP with POLRMT/TFAM/TFB2M plus respiration assays; functional enzyme screen with cholesterol-CHMP4B binding and perforin/NK/CAR-T killing assays plus c-Jun ChIP; recombinant mutant enzymology/stability with zebrafish mevalonic-acid rescue and exome sequencing\",\n      \"pmids\": [\"41545954\", \"42248910\", \"39531736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HMGCS1 is imported into mitochondria and nucleus is unresolved\", \"Whether mitochondrial/nuclear functions require catalytic activity not fully separated from metabolic effects\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined therapeutic targeting and downstream metabolic consequences, validating hymeglusin as a selective covalent HMGCS1 inhibitor whose effects mirror HMGCR loss, linking HMGCS1 to HIF-1α stabilization, GPX4/selenocysteine-tRNA-dependent ferroptosis, and steroidogenesis.\",\n      \"evidence\": \"activity-based protein profiling and chemical proteomics (preprint); RPL6 3'UTR binding with HIF-1α ubiquitination assays; cerulenin enzymatic inhibition with selenocysteine-tRNA/GPX4 analysis; transcriptomics/metabolomics with HMGCS1 inhibition in Sertoli cells\",\n      \"pmids\": [\"40631324\", \"40650669\", \"40848803\", \"40413863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sertoli-cell steroidogenesis link is correlative and from a non-human model\", \"Selectivity of cerulenin between FASN and HMGCS1 in cells not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signals and import machinery that direct HMGCS1 to the nucleus and mitochondria, and whether its moonlighting transcriptional and membrane-repair roles depend on catalysis versus protein scaffolding, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of compartment-specific HMGCS1 complexes\", \"Catalysis-dependent versus -independent moonlighting functions not cleanly separated\", \"Mechanism of regulated subcellular targeting unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [6, 14, 20, 24]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9, 22]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 14, 20, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 21, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CHMP4B\", \"PERK\", \"ACSS2\", \"ERRα\", \"LGALS7\", \"POLRMT\", \"TFAM\", \"TFB2M\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}