HMGCS1 Gene

Name	3-hydroxy-3-methylglutaryl-CoA synthase 1 (soluble)
Description	Enables protein homodimerization activity. Predicted to be involved in acetyl-CoA metabolic process and farnesyl diphosphate biosynthetic process, mevalonate pathway. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Mar 2025]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHMGCS1 is a cytosolic enzyme that catalyzes the condensation of acetyl‐CoA and acetoacetyl‐CoA to generate HMG‐CoA—a crucial step in the mevalonate pathway that ultimately leads to cholesterol biosynthesis. Structural studies of the human isoforms have provided fundamental insights enabling the design of isoform‐specific inhibitors with potential cholesterol‐reducing and antibiotic applications. In parallel, transcriptional regulation by proteins such as acyl‐CoA binding protein and RNA regulators like TDP‐43 influences HMGCS1 expression and thereby modulates cholesterol homeostasis in diverse cell types, including oligodendrocytes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical metabolic role, HMGCS1 has emerged as a key player in oncogenesis. In BRAFV600E‐driven cancers, for example, the HMGCS1–HMGCL–acetoacetate axis enhances MEK1 activation, promoting cell proliferation. Its upregulation has been closely associated with aggressive features and cancer stem cell enrichment in breast cancer, while in acute myeloid leukemia HMGCS1 confers chemoresistance by protecting mitochondrial and endoplasmic reticulum integrity under cellular stress. Pan‐cancer analyses further underscore its oncogenic functions, and studies in nasopharyngeal and cervical cancers indicate that both its metabolic activity (via cholesterol synthesis and acetoacetate production) and extra‐metabolic roles (through modulation of mitochondrial gene expression) contribute to therapeutic resistance and enhanced tumor progression. Moreover, in castration‐resistant prostate and hepatocellular carcinomas, deregulated HMGCS1—through mechanisms involving mRNA stability and protein stabilization—drives proliferation and resistance to frontline therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHMGCS1 is also implicated in various non‐malignant pathological conditions. In the context of vascular biology, reduced HMGCS1 expression in endothelial cells is associated with impaired angiogenesis, a defect that may contribute to the vascular dysfunction seen in preeclampsia. In dermatological disorders, its interaction with Galectin‐7 promotes cholesterol accumulation in keratinocytes, shedding light on the pathogenesis of normolipidemic cutaneous xanthoma, while in psoriasiform inflammation, HMGCS1 modulates keratinocyte proliferation and inflammatory cytokine production via the STAT3/IL‐23 axis. Moreover, tumor suppressive agents such as metformin have been shown to downregulate HMGCS1 through inhibition of transcription factors like NRF2, and a circular RNA derived from HMGCS1 (circHMGCS1) has been implicated in endothelial dysfunction linked to diabetes‐associated cardiovascular disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christina Vock, Frank Döring, Inke Nitz "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation of HMG-CoA synthase and HMG-CoA reductase genes by human ACBP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000185525"}], "href": "https://doi.org/10.1159/000185525"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19088433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19088433"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Naeem Shafqat, Andrew Turnbull, Johannes Zschocke, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.201910213"}], "href": "https://doi.org/10.1083/jcb.201910213"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34347016"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34347016"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Liang Zhao, Jun Fan, Siyuan Xia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HMG-CoA synthase 1 is a synthetic lethal partner of BRAF"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "V600E"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " in human cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M117.788778"}], "href": "https://doi.org/10.1074/jbc.M117.788778"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28468827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28468827"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Claire A Walsh, Nina Akrap, Elena Garre, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mevalonate precursor enzyme HMGCS1 is a novel marker and key mediator of cancer stem cell enrichment in luminal and basal models of breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0236187"}], "href": "https://doi.org/10.1371/journal.pone.0236187"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32692762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32692762"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Cheng Zhou, Jue Li, Juan Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2021.111378"}], "href": "https://doi.org/10.1016/j.biopha.2021.111378"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33601148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33601148"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Cheng Zhou, Zhiqin Wang, Yueqing Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pan-cancer analysis reveals the oncogenic role of 3-hydroxy-3-methylglutaryl-CoA synthase 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Rep (Hoboken) (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cnr2.1562"}], "href": "https://doi.org/10.1002/cnr2.1562"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34549901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34549901"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xiaomin Zhang, Congcong Sun, Jinliang Wan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Compartmentalized activities of HMGCS1 control cervical cancer radiosensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2022.110507"}], "href": "https://doi.org/10.1016/j.cellsig.2022.110507"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36328117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36328117"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Rui Zhou, Lin Qiu, Ling Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "P4HA1 activates HMGCS1 to promote nasopharyngeal carcinoma ferroptosis resistance and progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2023.110609"}], "href": "https://doi.org/10.1016/j.cellsig.2023.110609"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36702290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36702290"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Sheng-Jia Shi, Dong-Hui Han, Jing-Liang Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VIM‑AS1 promotes proliferation and drives enzalutamide resistance in prostate cancer via IGF2BP2‑mediated HMGCS1 mRNA stabilization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijo.2023.5482"}], "href": "https://doi.org/10.3892/ijo.2023.5482"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36734275"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36734275"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kai Li, Jiayu Zhang, Haiwen Lyu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Sci (Weinh) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/advs.202306827"}], "href": "https://doi.org/10.1002/advs.202306827"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38308184"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38308184"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Xiang Ying, Ying Zhu, Xiaoxiao Jin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Umbilical cord plasma-derived exosomes from preeclamptic women induce vascular dysfunction by targeting HMGCS1 in endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Placenta (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.placenta.2020.10.022"}], "href": "https://doi.org/10.1016/j.placenta.2020.10.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33120050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33120050"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Norihiro Fujimoto, Minoru Akiyama, Yasushi Satoh, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Circular RNA "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "HMGCS1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " sponges "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "MIR4521"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " to aggravate type 2 diabetes-induced vascular endothelial dysfunction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.97267"}], "href": "https://doi.org/10.7554/eLife.97267"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39235443"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39235443"}]}]}]}
Synonyms	HMGCS
Proteins	HMCS1_HUMAN
NCBI Gene ID	3157
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

HMGCS1 has 19,510 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 130 datasets.

Click the + buttons to view associations for HMGCS1 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

HMGCS1 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by HMGCS1 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HMGCS1 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of HMGCS1 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of HMGCS1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of HMGCS1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HMGCS1 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving HMGCS1 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of HMGCS1 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HMGCS1 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HMGCS1 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of HMGCS1 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of HMGCS1 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of HMGCS1 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with HMGCS1 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with HMGCS1 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HMGCS1 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of HMGCS1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of HMGCS1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of HMGCS1 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing HMGCS1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing HMGCS1 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing HMGCS1 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with HMGCS1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with HMGCS1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of HMGCS1 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with HMGCS1 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with HMGCS1 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with HMGCS1 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of HMGCS1 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with HMGCS1 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with HMGCS1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with HMGCS1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with HMGCS1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DrugBank Drug Targets	interacting drugs for HMGCS1 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at HMGCS1 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HMGCS1 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of HMGCS1 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing HMGCS1 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with HMGCS1 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with HMGCS1 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.