{"gene":"FDFT1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1994,"finding":"The FDFT1 (squalene synthase) gene was mapped to human chromosome 8p22-p23.1 using fluorescence in situ hybridization (FISH) with a YAC containing the gene, confirmed by PCR of somatic cell hybrids.","method":"FISH, somatic cell hybrid PCR mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct chromosomal localization by two orthogonal methods (FISH + somatic cell hybrid PCR), foundational mapping study","pmids":["8020937"],"is_preprint":false},{"year":2007,"finding":"The Fdft1 gene in rats harbors a hypomorphic allele (Fdft1(S)) with a missense nucleotide substitution that reduces cholesterol biosynthesis function; this allele is widely prevalent across laboratory rat strains and was identified as a determinant of hereditary cataracts in the SCR rat strain.","method":"Genetic screening, sequencing, functional characterization of mutant alleles","journal":"Experimental animals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-strain genetic screening with functional characterization, single lab","pmids":["17460354"],"is_preprint":false},{"year":2020,"finding":"FDFT1 acts as a tumor suppressor in colorectal cancer by negatively regulating AKT/mTOR/HIF1α signaling; fasting upregulates FDFT1 expression and inhibits aerobic glycolysis and proliferation in CRC cells through this pathway.","method":"Loss-of-function (siRNA knockdown), overexpression, in vitro proliferation/glycolysis assays, in vivo xenograft models, pathway inhibitor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including KD, OE, in vitro and in vivo assays with defined pathway readout, replicated across multiple CRC models","pmids":["32313017"],"is_preprint":false},{"year":2020,"finding":"Bavachinin inhibits FDFT1 expression via the AKT/mTOR/SREBP-2 pathway in HepaRG cells; overexpression of FDFT1 abolished bavachinin-induced inhibition of cholesterol synthesis, establishing FDFT1 as a downstream effector of this pathway in cholesterol regulation.","method":"Overexpression rescue experiments, Western blot, lipid accumulation assays, pathway inhibitor analysis","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression rescue and pathway analysis, single lab, two orthogonal methods","pmids":["32827918"],"is_preprint":false},{"year":2020,"finding":"miR-4425 directly targets FDFT1 mRNA to suppress its expression; forced FDFT1 expression negates the tumorigenic properties of miR-4425 in ovarian cancer cells, establishing FDFT1 as a functional target of miR-4425.","method":"Luciferase reporter assay, Western blot, siRNA knockdown, overexpression rescue, in vivo xenograft","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct target validation by luciferase reporter + Western blot + functional rescue experiments including in vivo model","pmids":["32877662"],"is_preprint":false},{"year":2024,"finding":"Somatic bi-allelic genetic and/or epigenetic (promoter hypermethylation) silencing of FDFT1 causes clonal expansion of FDFT1-deficient keratinocytes, resulting in porokeratosis; FDFT1-deficient keratinocytes showed cholesterol dependence for cell growth and altered cell-cycle and epidermal development gene expression. Topical statin treatment ameliorated lesions, confirming FDFT1's role in cholesterol synthesis in skin.","method":"Genomic sequencing, bisulfite sequencing (methylation analysis), IHC for FDFT1 localization in lesions, keratinocyte culture with cholesterol rescue, RT-PCR for gene expression","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (sequencing, methylation analysis, functional cell culture rescue, in vivo statin treatment), single rigorous study establishing mechanism","pmids":["38653249"],"is_preprint":false},{"year":2024,"finding":"Artemisitene (ATT) directly binds FDFT1 in breast cancer cells, as confirmed by CETSA, SPR, and molecular docking. Knockdown of FDFT1 induced NEDD4 expression and apoptosis via the TNFR1/NF-κB pathway; FDFT1 overexpression rescued ATT-induced apoptosis. ChIP assay showed p65 (NF-κB) regulates NEDD4 transcription downstream of FDFT1.","method":"CETSA, surface plasmon resonance (SPR), molecular docking, siRNA knockdown, overexpression rescue, ChIP assay, flow cytometry, Western blot","journal":"Phytomedicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding confirmed by multiple biophysical methods (CETSA + SPR), functional pathway established by KD/OE with mechanistic follow-up (ChIP), single rigorous study","pmids":["39461203"],"is_preprint":false},{"year":2024,"finding":"FDFT1 is transcriptionally regulated by SREBP2 (not SREBP1) in glioblastoma stem cells; FDFT1 activates the AKT pathway to regulate tumor metabolism and maintain stemness. Knockdown of FDFT1 suppressed proliferation, migration, and enhanced temozolomide sensitivity.","method":"RNA-seq, RT-qPCR, Western blot, siRNA knockdown, FDFT1 inhibitor (YM-53601), neurosphere formation assay, CCK8, transwell/wound healing assays","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation identified by RNA-seq/Western blot and functional KD experiments, single lab, multiple phenotypic readouts","pmids":["39707501"],"is_preprint":false},{"year":2024,"finding":"microRNA-146b-5p directly targets and downregulates FDFT1 in bladder cancer; FDFT1 suppression redirects its substrate (farnesyl diphosphate) toward the non-sterol branch of the mevalonate pathway, upregulating non-sterol branch genes and reducing total cholesterol, thereby promoting cisplatin resistance via activation of Ras/Rho family protein prenylation.","method":"Functional knockdown, ectopic overexpression, bioinformatics, rescue experiments, gene expression analysis of downstream pathway","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown/overexpression with rescue, downstream pathway gene expression characterization, single lab","pmids":["39270927"],"is_preprint":false},{"year":2025,"finding":"FDFT1 knockdown in HCC decreases cholesterol and bile acid levels, increases HNF4A transcriptional activity, which promotes ALDOB transcription; ALDOB then binds AKT1 and inhibits AKT1 phosphorylation, delaying HCC progression. This HNF4A/ALDOB/AKT1 axis was established as the mechanistic pathway downstream of FDFT1.","method":"siRNA knockdown, overexpression, in vitro and in vivo experiments, ChIP/promoter binding assays, co-immunoprecipitation (ALDOB-AKT1), AKT inhibitor combination, cholesterol/bile acid quantification","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (KD/OE in vitro+in vivo, Co-IP, promoter binding, metabolite quantification, pharmacological rescue), defining a full mechanistic axis","pmids":["39899681"],"is_preprint":false},{"year":2025,"finding":"NeuroD1 binds the FDFT1 promoter and activates FDFT1 transcription; this is mediated through KAT2A-catalyzed H3K27 acetylation at the FDFT1 locus, linking NeuroD1-driven histone acetylation to cholesterol biosynthesis in HCC.","method":"ChIP assay (NeuroD1 binding to FDFT1 promoter), Western blot, RT-qPCR, KAT2A activity assays, loss-of-function/overexpression experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming promoter binding and H3K27ac, functional KD/OE experiments, single lab","pmids":["40890513"],"is_preprint":false},{"year":2025,"finding":"THEM6 stabilizes FDFT1 protein by interacting with HSP90 to protect FDFT1 from K48-linked ubiquitination and endoplasmic reticulum-associated degradation (ERAD), thereby prolonging FDFT1 protein half-life and increasing intracellular cholesterol biosynthesis; elevated cholesterol from this mechanism decreases ferroptosis susceptibility in TNBC cells.","method":"Co-immunoprecipitation (THEM6-HSP90, FDFT1 ubiquitination), Western blot, protein half-life analysis, siRNA knockdown, overexpression, in vitro and in vivo (xenograft) functional assays, ferroptosis markers (GPX4, SLC7A11, ACSL4, ROS, MDA)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP establishing protein interactions, ubiquitination assay, protein stability (half-life) measurement, functional in vitro+in vivo rescue, single rigorous study with multiple orthogonal methods","pmids":["40931051"],"is_preprint":false},{"year":2025,"finding":"FDFT1 acts as a negative regulator of autophagy in HCC cells; loss of FDFT1 increased autophagosome formation and lysosomal fusion, while FDFT1 overexpression suppressed basal and induced autophagy through AMPK-ULK1 signaling.","method":"siRNA knockdown, overexpression, autophagosome imaging, Western blot for AMPK-ULK1 pathway markers","journal":"Biomolecules & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined pathway readout (AMPK-ULK1), single lab, multiple autophagy readouts","pmids":["42059033"],"is_preprint":false},{"year":2025,"finding":"In colorectal cancer, atorvastatin activates the SREBP2-FDFT1 axis (by depleting cellular cholesterol via HMGCR inhibition), and FDFT1-mediated inhibition of the PI3K/AKT pathway induces ER stress, autophagy, and ferroptosis to promote lipid catabolism.","method":"In vivo AOM/DSS CRC mouse model, Western blot, pathway analysis, FDFT1 overexpression/knockdown","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with mechanistic pathway analysis and FDFT1 functional manipulation, single lab","pmids":["41866501"],"is_preprint":false},{"year":2024,"finding":"In chicken theca cells, estrogen promotes FDFT1 expression via GSK3β phosphorylation at Tyr216, which enhances binding of GSK3β to LSD1, increasing LSD1Ser54 phosphorylation; elevated LSD1Ser54p then activates FDFT1 transcription, promoting cholesterol biosynthesis.","method":"CUT&RUN sequencing, transcriptome sequencing, overexpression/knockdown, Western blot, co-immunoprecipitation (GSK3β-LSD1), RT-qPCR","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, CUT&RUN, and transcriptomics establishing mechanism, single lab","pmids":["39595520"],"is_preprint":false},{"year":2025,"finding":"HIV-1 Tat downregulates FDFT1 expression in BCBL-1 cells, reducing cellular cholesterol levels; FDFT1 knockdown upregulates KSHV lytic reactivation genes (ORF50) while FDFT1 overexpression upregulates latency gene (ORF73), establishing FDFT1-mediated cholesterol regulation as a modulator of KSHV replication state.","method":"Lentiviral overexpression/RNAi knockdown, RT-qPCR, cholesterol assay","journal":"Current HIV research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown/overexpression with gene expression readout only, no direct mechanistic biochemical confirmation","pmids":["40947702"],"is_preprint":false},{"year":2025,"finding":"piR-39980 targets FDFT1, and suppression of FDFT1 leads to inhibition of CYPOR and the EIF3H/HIF1α axis; CYPOR inhibition increases doxorubicin accumulation, and EIF3H/HIF1α axis inhibition induces DNA break-mediated apoptosis, thereby enhancing doxorubicin sensitivity in tongue cancer cells.","method":"Dual luciferase assay, Western blot, RT-qPCR, flow cytometry, migration assays, molecular assays for CYPOR and HIF1α","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validation of piRNA-FDFT1 targeting, functional cascade established by knockdown with pathway markers, single lab","pmids":["40339976"],"is_preprint":false},{"year":2025,"finding":"Squalene synthase (SQS/FDFT1) inhibition in lung cancer cells using pharmacological inhibitors suppressed tumor growth in vivo and reduced lung inflammation and tumor burden, providing evidence that SQS is a functionally important enzyme target in lung cancer.","method":"In vitro cancer cell assays with SQS inhibitors, in vivo tumor burden and lung inflammation models","journal":"ACS medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition in vitro and in vivo with functional tumor readout, two chemically diverse inhibitors used, single lab","pmids":["41089479"],"is_preprint":false},{"year":2025,"finding":"METTL7A directly binds SREBP1 and SCAP, hindering nuclear translocation of SREBP1, thereby reducing expression of FDFT1 (and other cholesterol synthesis genes SQLE, CYP51A1) and intracellular cholesterol content in colorectal cancer cells.","method":"Co-immunoprecipitation (METTL7A-SREBP1, METTL7A-SCAP), Western blot, immunofluorescence, transcriptomics, proteomics, in vitro and in vivo functional assays","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing direct binding, transcriptomics/proteomics for downstream effects, single lab with multiple methods","pmids":["42009961"],"is_preprint":false}],"current_model":"FDFT1 (squalene synthase) encodes the first enzyme committed uniquely to sterol biosynthesis, catalyzing condensation of two farnesyl diphosphate molecules to form squalene; it is mapped to human chromosome 8p22-p23.1, localized to the ER membrane, and functions as a metabolic hub whose activity level regulates cholesterol and bile acid pools to modulate downstream signaling through multiple axes including AKT/mTOR/HIF1α, HNF4A/ALDOB/AKT1, AMPK-ULK1 (autophagy), and TNFR1/NF-κB/NEDD4; its transcription is activated by SREBP2, NeuroD1 (via KAT2A-H3K27ac), and estrogen (via GSK3β/LSD1Ser54p), while it is post-translationally stabilized by EMC2/HSP90 protection from ERAD and its substrate flux can be redirected to non-sterol prenylation branches when FDFT1 is suppressed, thereby modulating ferroptosis susceptibility and chemoresistance."},"narrative":{"mechanistic_narrative":"FDFT1 (squalene synthase) is the committed enzyme of sterol biosynthesis, catalyzing condensation of two farnesyl diphosphate molecules to form squalene, and its activity functions as a metabolic rheostat that sets cellular cholesterol and bile acid pools to modulate downstream growth, survival, and stress signaling [PMID:32313017, PMID:39899681]. The gene was mapped to human chromosome 8p22-p23.1 [PMID:8020937], and its enzymatic function in sterol synthesis is directly demonstrated by the finding that bi-allelic somatic silencing of FDFT1 drives clonal expansion of cholesterol-dependent keratinocytes to cause porokeratosis, lesions ameliorated by topical statin treatment [PMID:38653249]. In multiple cancers FDFT1 behaves as a tumor suppressor: it restrains AKT/mTOR/HIF1α signaling and aerobic glycolysis [PMID:32313017], and in hepatocellular carcinoma its cholesterol/bile-acid output suppresses HNF4A-driven ALDOB transcription, where ALDOB binds AKT1 to block its phosphorylation [PMID:39899681]. FDFT1-derived cholesterol also negatively regulates autophagy via AMPK-ULK1 [PMID:42059033], suppresses NEDD4 induction through the TNFR1/NF-κB axis [PMID:39461203], and lowers ferroptosis susceptibility [PMID:40931051]. FDFT1 transcription is driven by SREBP2 [PMID:39707501] and additional inputs including NeuroD1 acting through KAT2A-mediated H3K27 acetylation [PMID:40890513], while its protein level is set post-translationally by THEM6/HSP90, which shields FDFT1 from K48-ubiquitination and ER-associated degradation [PMID:40931051]. When FDFT1 is suppressed, farnesyl diphosphate flux is redirected to the non-sterol prenylation branch of the mevalonate pathway, activating Ras/Rho prenylation and promoting chemoresistance [PMID:39270927].","teleology":[{"year":1994,"claim":"Establishing the chromosomal location of the human squalene synthase gene provided the genomic anchor for all subsequent functional and disease studies.","evidence":"FISH with a YAC clone plus somatic cell hybrid PCR mapping","pmids":["8020937"],"confidence":"High","gaps":["Mapping alone established no enzymatic or regulatory function","No protein-level characterization in this study"]},{"year":2007,"claim":"A hypomorphic Fdft1 allele linking reduced cholesterol biosynthesis to hereditary cataract demonstrated that FDFT1 activity level is physiologically dose-sensitive in vivo.","evidence":"Genetic screening and sequencing of mutant rat alleles with functional characterization","pmids":["17460354"],"confidence":"Medium","gaps":["Mechanistic link between sterol depletion and cataract not resolved","Findings in rat strains, not human"]},{"year":2020,"claim":"Loss- and gain-of-function studies recast FDFT1 from a housekeeping enzyme into a tumor suppressor that actively restrains oncogenic AKT/mTOR/HIF1α signaling and glycolysis.","evidence":"siRNA knockdown, overexpression, glycolysis assays and xenografts in CRC; miRNA/SREBP-2-axis rescue experiments in CRC, hepatic and ovarian models","pmids":["32313017","32827918","32877662"],"confidence":"High","gaps":["How an ER sterol enzyme mechanistically suppresses AKT/mTOR not fully resolved at this stage","Relative contribution of cholesterol depletion versus FPP accumulation unclear"]},{"year":2024,"claim":"Direct small-molecule binding and transcriptional mapping defined how FDFT1 is controlled and how its loss triggers cell death, identifying the TNFR1/NF-κB/NEDD4 apoptotic axis and SREBP2 as its principal transcriptional driver.","evidence":"CETSA/SPR/docking for direct artemisitene binding plus ChIP in breast cancer; RNA-seq, inhibitor (YM-53601) and knockdown in glioblastoma stem cells","pmids":["39461203","39707501"],"confidence":"High","gaps":["Whether NEDD4 induction depends on cholesterol depletion or direct FDFT1 enzymatic activity not separated","SREBP2 regulation studied in single tumor context"]},{"year":2024,"claim":"Identification of estrogen-GSK3β-LSD1 and microRNA inputs showed FDFT1 transcription is set by hormonal and epigenetic signals, and that its suppression reroutes substrate to non-sterol prenylation to drive chemoresistance.","evidence":"CUT&RUN, Co-IP and transcriptomics in chicken theca cells; luciferase, knockdown and pathway gene expression in bladder cancer","pmids":["39595520","39270927"],"confidence":"Medium","gaps":["FPP rerouting inferred from pathway gene expression, not direct metabolite flux measurement","Estrogen axis characterized in avian cells only"]},{"year":2024,"claim":"Discovery that bi-allelic somatic silencing of FDFT1 causes porokeratosis provided direct in-human disease evidence that FDFT1-driven cholesterol synthesis is required for normal keratinocyte homeostasis.","evidence":"Genomic and bisulfite sequencing, IHC, keratinocyte cholesterol rescue and topical statin treatment","pmids":["38653249"],"confidence":"High","gaps":["Mechanism connecting cholesterol dependence to clonal expansion and cell-cycle change not fully resolved"]},{"year":2025,"claim":"Mechanistic dissection in HCC and TNBC defined the downstream effector axes and the post-translational control of FDFT1 — the HNF4A/ALDOB/AKT1 axis, AMPK-ULK1 autophagy suppression, and THEM6/HSP90-mediated protection from ERAD.","evidence":"Co-IP, promoter binding, metabolite quantification and pharmacological rescue in HCC; ubiquitination assays, protein half-life and ferroptosis readouts in TNBC; autophagosome imaging and AMPK-ULK1 blotting","pmids":["39899681","40931051","42059033","40890513"],"confidence":"High","gaps":["Whether the same axes operate outside liver and breast contexts untested","How cholesterol level mechanistically modulates HNF4A activity not fully defined"]},{"year":2025,"claim":"Pharmacological and viral studies extended FDFT1's reach to statin-induced anti-tumor responses, additional non-coding RNA regulation, and modulation of viral replication state through cholesterol.","evidence":"AOM/DSS CRC model with atorvastatin; SQS inhibitors in lung cancer; piR-39980 luciferase/knockdown in tongue cancer; METTL7A-SREBP1 Co-IP in CRC; HIV-1 Tat/KSHV expression assays","pmids":["41866501","41089479","40339976","42009961","40947702"],"confidence":"Medium","gaps":["KSHV/HIV link rests on expression readouts without biochemical confirmation","Tissue-specificity of the many regulatory inputs not reconciled into one model"]},{"year":null,"claim":"It remains unresolved whether FDFT1's growth-suppressive effects derive primarily from cholesterol/bile-acid depletion, from accumulation of the farnesyl-diphosphate substrate redirected to prenylation, or from a non-catalytic scaffolding role, and how its context-dependent tumor-suppressor versus stemness-promoting functions are reconciled.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of FDFT1 in any signaling complex in the corpus","Direct flux measurements separating sterol from prenylation contributions are lacking","Reconciliation of opposing tumor-context roles unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,5,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,13]}],"complexes":[],"partners":["THEM6","HSP90"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P37268","full_name":"Squalene synthase","aliases":["FPP:FPP farnesyltransferase","Farnesyl-diphosphate farnesyltransferase","Farnesyl-diphosphate farnesyltransferase 1"],"length_aa":417,"mass_kda":48.1,"function":"Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP) moieties to form squalene. Proceeds in two distinct steps. In the first half-reaction, two molecules of FPP react to form the stable presqualene diphosphate intermediate (PSQPP), with concomitant release of a proton and a molecule of inorganic diphosphate. In the second half-reaction, PSQPP undergoes heterolysis, isomerization, and reduction with NADPH or NADH to form squalene. It is the first committed enzyme of the sterol biosynthesis pathway","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P37268/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FDFT1","classification":"Not Classified","n_dependent_lines":125,"n_total_lines":1208,"dependency_fraction":0.10347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FDFT1","total_profiled":1310},"omim":[{"mim_id":"618156","title":"SQUALENE SYNTHASE DEFICIENCY; SQSD","url":"https://www.omim.org/entry/618156"},{"mim_id":"600909","title":"LANOSTEROL SYNTHASE; LSS","url":"https://www.omim.org/entry/600909"},{"mim_id":"184420","title":"FARNESYLDIPHOSPHATE FARNESYLTRANSFERASE 1; FDFT1","url":"https://www.omim.org/entry/184420"},{"mim_id":"179613","title":"RECOMBINANT CHROMOSOME 8 SYNDROME","url":"https://www.omim.org/entry/179613"},{"mim_id":"148370","title":"KERATOLYTIC WINTER ERYTHEMA; KWE","url":"https://www.omim.org/entry/148370"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FDFT1"},"hgnc":{"alias_symbol":["SQS"],"prev_symbol":[]},"alphafold":{"accession":"P37268","domains":[{"cath_id":"1.10.600.10","chopping":"38-160","consensus_level":"medium","plddt":95.9954,"start":38,"end":160},{"cath_id":"1.10.600.10","chopping":"161-373","consensus_level":"medium","plddt":96.0799,"start":161,"end":373}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P37268","model_url":"https://alphafold.ebi.ac.uk/files/AF-P37268-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P37268-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FDFT1","jax_strain_url":"https://www.jax.org/strain/search?query=FDFT1"},"sequence":{"accession":"P37268","fasta_url":"https://rest.uniprot.org/uniprotkb/P37268.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P37268/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P37268"}},"corpus_meta":[{"pmid":"32313017","id":"PMC_32313017","title":"Fasting 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8p22-p23.1.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8020937","citation_count":27,"is_preprint":false},{"pmid":"30468409","id":"PMC_30468409","title":"Characterization of farnesyl diphosphate farnesyl transferase 1 (FDFT1) expression in cancer.","date":"2018","source":"Personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30468409","citation_count":25,"is_preprint":false},{"pmid":"35322581","id":"PMC_35322581","title":"Identification of FDFT1 as a potential biomarker associated with ferroptosis in ccRCC.","date":"2022","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35322581","citation_count":24,"is_preprint":false},{"pmid":"35093030","id":"PMC_35093030","title":"Raman spectroscopy biochemical characterisation of bladder cancer cisplatin resistance regulated by FDFT1: a review.","date":"2022","source":"Cellular & molecular biology 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BCR","url":"https://pubmed.ncbi.nlm.nih.gov/40619388","citation_count":4,"is_preprint":false},{"pmid":"39270927","id":"PMC_39270927","title":"MicroRNA-146b-5p/FDFT1 mediates cisplatin sensitivity in bladder cancer by redirecting cholesterol biosynthesis to the non-sterol branch.","date":"2024","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39270927","citation_count":4,"is_preprint":false},{"pmid":"40438588","id":"PMC_40438588","title":"Valproic acid induces ferroptosis and suppresses the proliferation of MDA-MB-231 cells by targeting FDFT1.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40438588","citation_count":4,"is_preprint":false},{"pmid":"40206734","id":"PMC_40206734","title":"Identification of FDFT1 and PGRMC1 as New Biomarkers in Nonalcoholic Steatohepatitis (NASH)-Related Hepatocellular Carcinoma by Deep Learning.","date":"2025","source":"Journal of hepatocellular carcinoma","url":"https://pubmed.ncbi.nlm.nih.gov/40206734","citation_count":3,"is_preprint":false},{"pmid":"39595520","id":"PMC_39595520","title":"Estrogen Enhances FDFT1 Expression in Theca Cells of Chicken Hierarchical Ovarian Follicles by Increasing LSD1Ser54p Level Through GSK3β Phosphorylation at 216th Tyrosine.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39595520","citation_count":3,"is_preprint":false},{"pmid":"40339976","id":"PMC_40339976","title":"A piRNA chemosensitizes doxorubicin in tongue squamous cell carcinoma by targeting FDFT1 and inhibiting the EIF3H/HIF1α/CYPOR axis.","date":"2025","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40339976","citation_count":3,"is_preprint":false},{"pmid":"40931051","id":"PMC_40931051","title":"EMC2 promotes triple negative breast cancer growth by protecting FDFT1 from endoplasmic reticulum associated degradation to impair ferroptosis susceptibility.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40931051","citation_count":2,"is_preprint":false},{"pmid":"38810354","id":"PMC_38810354","title":"Spectroscopic diagnosis and metabolite characterization of cisplatin resistance regulated by FDFT1 in bladder cancer tissue.","date":"2024","source":"Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38810354","citation_count":2,"is_preprint":false},{"pmid":"40947702","id":"PMC_40947702","title":"Impact of HIV-1 Tat on FDFT1 Suppression, Changes in Cholesterol Level, and KSHV Replication in BCBL1 Cells.","date":"2025","source":"Current HIV research","url":"https://pubmed.ncbi.nlm.nih.gov/40947702","citation_count":2,"is_preprint":false},{"pmid":"19894527","id":"PMC_19894527","title":"[Culture of transgenic Glycyrrhiza uralensis hairy root with licorice squalene synthase (SQS) gene].","date":"2009","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/19894527","citation_count":2,"is_preprint":false},{"pmid":"35477128","id":"PMC_35477128","title":"FDFT1/FGFR2 rearrangement: A newly identified anlotinib-sensitive FGFR2 variant in cholangiocarcinoma.","date":"2022","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35477128","citation_count":1,"is_preprint":false},{"pmid":"41009671","id":"PMC_41009671","title":"Discovery of an SQS-PSY Domain-Containing Protein in Meloidogyne incognita Reveals Its Function in Parasitism.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41009671","citation_count":0,"is_preprint":false},{"pmid":"41089479","id":"PMC_41089479","title":"Unraveling the Potential Pathogenic Role of Squalene Synthase (SQS) in Lung Cancer Using Enzyme Inhibitors as Molecular Tools.","date":"2025","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/41089479","citation_count":0,"is_preprint":false},{"pmid":"42059033","id":"PMC_42059033","title":"FDFT1 Acts as a Negative Regulator of Autophagy by Modulating AMPK-ULK1 Signaling in Hepatocellular Carcinoma Cells.","date":"2025","source":"Biomolecules & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/42059033","citation_count":0,"is_preprint":false},{"pmid":"42009961","id":"PMC_42009961","title":"METTL7A inhibits progression of colorectal cancer through the SREBP1 / FDFT1 / SQLE / CYP51A1 / cholesterol metabolic pathway.","date":"2026","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/42009961","citation_count":0,"is_preprint":false},{"pmid":"30406769","id":"PMC_30406769","title":"Optimizing special quasirandom structure (SQS) models for accurate functional property prediction in disordered 2D alloys.","date":"2018","source":"Journal of physics. Condensed matter : an Institute of Physics journal","url":"https://pubmed.ncbi.nlm.nih.gov/30406769","citation_count":0,"is_preprint":false},{"pmid":"41866501","id":"PMC_41866501","title":"Atorvastatin promotes lipid catabolism in colorectal cancer via FDFT1‒mediated inhibition of the PI3K/AKT pathway.","date":"2026","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41866501","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24564,"output_tokens":4793,"usd":0.072793,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13034,"output_tokens":3330,"usd":0.07421,"stage2_stop_reason":"end_turn"},"total_usd":0.147003,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"The FDFT1 (squalene synthase) gene was mapped to human chromosome 8p22-p23.1 using fluorescence in situ hybridization (FISH) with a YAC containing the gene, confirmed by PCR of somatic cell hybrids.\",\n      \"method\": \"FISH, somatic cell hybrid PCR mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct chromosomal localization by two orthogonal methods (FISH + somatic cell hybrid PCR), foundational mapping study\",\n      \"pmids\": [\"8020937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The Fdft1 gene in rats harbors a hypomorphic allele (Fdft1(S)) with a missense nucleotide substitution that reduces cholesterol biosynthesis function; this allele is widely prevalent across laboratory rat strains and was identified as a determinant of hereditary cataracts in the SCR rat strain.\",\n      \"method\": \"Genetic screening, sequencing, functional characterization of mutant alleles\",\n      \"journal\": \"Experimental animals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-strain genetic screening with functional characterization, single lab\",\n      \"pmids\": [\"17460354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FDFT1 acts as a tumor suppressor in colorectal cancer by negatively regulating AKT/mTOR/HIF1α signaling; fasting upregulates FDFT1 expression and inhibits aerobic glycolysis and proliferation in CRC cells through this pathway.\",\n      \"method\": \"Loss-of-function (siRNA knockdown), overexpression, in vitro proliferation/glycolysis assays, in vivo xenograft models, pathway inhibitor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including KD, OE, in vitro and in vivo assays with defined pathway readout, replicated across multiple CRC models\",\n      \"pmids\": [\"32313017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Bavachinin inhibits FDFT1 expression via the AKT/mTOR/SREBP-2 pathway in HepaRG cells; overexpression of FDFT1 abolished bavachinin-induced inhibition of cholesterol synthesis, establishing FDFT1 as a downstream effector of this pathway in cholesterol regulation.\",\n      \"method\": \"Overexpression rescue experiments, Western blot, lipid accumulation assays, pathway inhibitor analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression rescue and pathway analysis, single lab, two orthogonal methods\",\n      \"pmids\": [\"32827918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-4425 directly targets FDFT1 mRNA to suppress its expression; forced FDFT1 expression negates the tumorigenic properties of miR-4425 in ovarian cancer cells, establishing FDFT1 as a functional target of miR-4425.\",\n      \"method\": \"Luciferase reporter assay, Western blot, siRNA knockdown, overexpression rescue, in vivo xenograft\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct target validation by luciferase reporter + Western blot + functional rescue experiments including in vivo model\",\n      \"pmids\": [\"32877662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Somatic bi-allelic genetic and/or epigenetic (promoter hypermethylation) silencing of FDFT1 causes clonal expansion of FDFT1-deficient keratinocytes, resulting in porokeratosis; FDFT1-deficient keratinocytes showed cholesterol dependence for cell growth and altered cell-cycle and epidermal development gene expression. Topical statin treatment ameliorated lesions, confirming FDFT1's role in cholesterol synthesis in skin.\",\n      \"method\": \"Genomic sequencing, bisulfite sequencing (methylation analysis), IHC for FDFT1 localization in lesions, keratinocyte culture with cholesterol rescue, RT-PCR for gene expression\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (sequencing, methylation analysis, functional cell culture rescue, in vivo statin treatment), single rigorous study establishing mechanism\",\n      \"pmids\": [\"38653249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Artemisitene (ATT) directly binds FDFT1 in breast cancer cells, as confirmed by CETSA, SPR, and molecular docking. Knockdown of FDFT1 induced NEDD4 expression and apoptosis via the TNFR1/NF-κB pathway; FDFT1 overexpression rescued ATT-induced apoptosis. ChIP assay showed p65 (NF-κB) regulates NEDD4 transcription downstream of FDFT1.\",\n      \"method\": \"CETSA, surface plasmon resonance (SPR), molecular docking, siRNA knockdown, overexpression rescue, ChIP assay, flow cytometry, Western blot\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding confirmed by multiple biophysical methods (CETSA + SPR), functional pathway established by KD/OE with mechanistic follow-up (ChIP), single rigorous study\",\n      \"pmids\": [\"39461203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FDFT1 is transcriptionally regulated by SREBP2 (not SREBP1) in glioblastoma stem cells; FDFT1 activates the AKT pathway to regulate tumor metabolism and maintain stemness. Knockdown of FDFT1 suppressed proliferation, migration, and enhanced temozolomide sensitivity.\",\n      \"method\": \"RNA-seq, RT-qPCR, Western blot, siRNA knockdown, FDFT1 inhibitor (YM-53601), neurosphere formation assay, CCK8, transwell/wound healing assays\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation identified by RNA-seq/Western blot and functional KD experiments, single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"39707501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"microRNA-146b-5p directly targets and downregulates FDFT1 in bladder cancer; FDFT1 suppression redirects its substrate (farnesyl diphosphate) toward the non-sterol branch of the mevalonate pathway, upregulating non-sterol branch genes and reducing total cholesterol, thereby promoting cisplatin resistance via activation of Ras/Rho family protein prenylation.\",\n      \"method\": \"Functional knockdown, ectopic overexpression, bioinformatics, rescue experiments, gene expression analysis of downstream pathway\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown/overexpression with rescue, downstream pathway gene expression characterization, single lab\",\n      \"pmids\": [\"39270927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FDFT1 knockdown in HCC decreases cholesterol and bile acid levels, increases HNF4A transcriptional activity, which promotes ALDOB transcription; ALDOB then binds AKT1 and inhibits AKT1 phosphorylation, delaying HCC progression. This HNF4A/ALDOB/AKT1 axis was established as the mechanistic pathway downstream of FDFT1.\",\n      \"method\": \"siRNA knockdown, overexpression, in vitro and in vivo experiments, ChIP/promoter binding assays, co-immunoprecipitation (ALDOB-AKT1), AKT inhibitor combination, cholesterol/bile acid quantification\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (KD/OE in vitro+in vivo, Co-IP, promoter binding, metabolite quantification, pharmacological rescue), defining a full mechanistic axis\",\n      \"pmids\": [\"39899681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NeuroD1 binds the FDFT1 promoter and activates FDFT1 transcription; this is mediated through KAT2A-catalyzed H3K27 acetylation at the FDFT1 locus, linking NeuroD1-driven histone acetylation to cholesterol biosynthesis in HCC.\",\n      \"method\": \"ChIP assay (NeuroD1 binding to FDFT1 promoter), Western blot, RT-qPCR, KAT2A activity assays, loss-of-function/overexpression experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming promoter binding and H3K27ac, functional KD/OE experiments, single lab\",\n      \"pmids\": [\"40890513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THEM6 stabilizes FDFT1 protein by interacting with HSP90 to protect FDFT1 from K48-linked ubiquitination and endoplasmic reticulum-associated degradation (ERAD), thereby prolonging FDFT1 protein half-life and increasing intracellular cholesterol biosynthesis; elevated cholesterol from this mechanism decreases ferroptosis susceptibility in TNBC cells.\",\n      \"method\": \"Co-immunoprecipitation (THEM6-HSP90, FDFT1 ubiquitination), Western blot, protein half-life analysis, siRNA knockdown, overexpression, in vitro and in vivo (xenograft) functional assays, ferroptosis markers (GPX4, SLC7A11, ACSL4, ROS, MDA)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP establishing protein interactions, ubiquitination assay, protein stability (half-life) measurement, functional in vitro+in vivo rescue, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"40931051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FDFT1 acts as a negative regulator of autophagy in HCC cells; loss of FDFT1 increased autophagosome formation and lysosomal fusion, while FDFT1 overexpression suppressed basal and induced autophagy through AMPK-ULK1 signaling.\",\n      \"method\": \"siRNA knockdown, overexpression, autophagosome imaging, Western blot for AMPK-ULK1 pathway markers\",\n      \"journal\": \"Biomolecules & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined pathway readout (AMPK-ULK1), single lab, multiple autophagy readouts\",\n      \"pmids\": [\"42059033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colorectal cancer, atorvastatin activates the SREBP2-FDFT1 axis (by depleting cellular cholesterol via HMGCR inhibition), and FDFT1-mediated inhibition of the PI3K/AKT pathway induces ER stress, autophagy, and ferroptosis to promote lipid catabolism.\",\n      \"method\": \"In vivo AOM/DSS CRC mouse model, Western blot, pathway analysis, FDFT1 overexpression/knockdown\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with mechanistic pathway analysis and FDFT1 functional manipulation, single lab\",\n      \"pmids\": [\"41866501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In chicken theca cells, estrogen promotes FDFT1 expression via GSK3β phosphorylation at Tyr216, which enhances binding of GSK3β to LSD1, increasing LSD1Ser54 phosphorylation; elevated LSD1Ser54p then activates FDFT1 transcription, promoting cholesterol biosynthesis.\",\n      \"method\": \"CUT&RUN sequencing, transcriptome sequencing, overexpression/knockdown, Western blot, co-immunoprecipitation (GSK3β-LSD1), RT-qPCR\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, CUT&RUN, and transcriptomics establishing mechanism, single lab\",\n      \"pmids\": [\"39595520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIV-1 Tat downregulates FDFT1 expression in BCBL-1 cells, reducing cellular cholesterol levels; FDFT1 knockdown upregulates KSHV lytic reactivation genes (ORF50) while FDFT1 overexpression upregulates latency gene (ORF73), establishing FDFT1-mediated cholesterol regulation as a modulator of KSHV replication state.\",\n      \"method\": \"Lentiviral overexpression/RNAi knockdown, RT-qPCR, cholesterol assay\",\n      \"journal\": \"Current HIV research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown/overexpression with gene expression readout only, no direct mechanistic biochemical confirmation\",\n      \"pmids\": [\"40947702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"piR-39980 targets FDFT1, and suppression of FDFT1 leads to inhibition of CYPOR and the EIF3H/HIF1α axis; CYPOR inhibition increases doxorubicin accumulation, and EIF3H/HIF1α axis inhibition induces DNA break-mediated apoptosis, thereby enhancing doxorubicin sensitivity in tongue cancer cells.\",\n      \"method\": \"Dual luciferase assay, Western blot, RT-qPCR, flow cytometry, migration assays, molecular assays for CYPOR and HIF1α\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validation of piRNA-FDFT1 targeting, functional cascade established by knockdown with pathway markers, single lab\",\n      \"pmids\": [\"40339976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Squalene synthase (SQS/FDFT1) inhibition in lung cancer cells using pharmacological inhibitors suppressed tumor growth in vivo and reduced lung inflammation and tumor burden, providing evidence that SQS is a functionally important enzyme target in lung cancer.\",\n      \"method\": \"In vitro cancer cell assays with SQS inhibitors, in vivo tumor burden and lung inflammation models\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition in vitro and in vivo with functional tumor readout, two chemically diverse inhibitors used, single lab\",\n      \"pmids\": [\"41089479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL7A directly binds SREBP1 and SCAP, hindering nuclear translocation of SREBP1, thereby reducing expression of FDFT1 (and other cholesterol synthesis genes SQLE, CYP51A1) and intracellular cholesterol content in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (METTL7A-SREBP1, METTL7A-SCAP), Western blot, immunofluorescence, transcriptomics, proteomics, in vitro and in vivo functional assays\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing direct binding, transcriptomics/proteomics for downstream effects, single lab with multiple methods\",\n      \"pmids\": [\"42009961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FDFT1 (squalene synthase) encodes the first enzyme committed uniquely to sterol biosynthesis, catalyzing condensation of two farnesyl diphosphate molecules to form squalene; it is mapped to human chromosome 8p22-p23.1, localized to the ER membrane, and functions as a metabolic hub whose activity level regulates cholesterol and bile acid pools to modulate downstream signaling through multiple axes including AKT/mTOR/HIF1α, HNF4A/ALDOB/AKT1, AMPK-ULK1 (autophagy), and TNFR1/NF-κB/NEDD4; its transcription is activated by SREBP2, NeuroD1 (via KAT2A-H3K27ac), and estrogen (via GSK3β/LSD1Ser54p), while it is post-translationally stabilized by EMC2/HSP90 protection from ERAD and its substrate flux can be redirected to non-sterol prenylation branches when FDFT1 is suppressed, thereby modulating ferroptosis susceptibility and chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FDFT1 (squalene synthase) is the committed enzyme of sterol biosynthesis, catalyzing condensation of two farnesyl diphosphate molecules to form squalene, and its activity functions as a metabolic rheostat that sets cellular cholesterol and bile acid pools to modulate downstream growth, survival, and stress signaling [#2, #9]. The gene was mapped to human chromosome 8p22-p23.1 [#0], and its enzymatic function in sterol synthesis is directly demonstrated by the finding that bi-allelic somatic silencing of FDFT1 drives clonal expansion of cholesterol-dependent keratinocytes to cause porokeratosis, lesions ameliorated by topical statin treatment [#5]. In multiple cancers FDFT1 behaves as a tumor suppressor: it restrains AKT/mTOR/HIF1\\u03b1 signaling and aerobic glycolysis [#2], and in hepatocellular carcinoma its cholesterol/bile-acid output suppresses HNF4A-driven ALDOB transcription, where ALDOB binds AKT1 to block its phosphorylation [#9]. FDFT1-derived cholesterol also negatively regulates autophagy via AMPK-ULK1 [#12], suppresses NEDD4 induction through the TNFR1/NF-\\u03baB axis [#6], and lowers ferroptosis susceptibility [#11]. FDFT1 transcription is driven by SREBP2 [#7] and additional inputs including NeuroD1 acting through KAT2A-mediated H3K27 acetylation [#10], while its protein level is set post-translationally by THEM6/HSP90, which shields FDFT1 from K48-ubiquitination and ER-associated degradation [#11]. When FDFT1 is suppressed, farnesyl diphosphate flux is redirected to the non-sterol prenylation branch of the mevalonate pathway, activating Ras/Rho prenylation and promoting chemoresistance [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the chromosomal location of the human squalene synthase gene provided the genomic anchor for all subsequent functional and disease studies.\",\n      \"evidence\": \"FISH with a YAC clone plus somatic cell hybrid PCR mapping\",\n      \"pmids\": [\"8020937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mapping alone established no enzymatic or regulatory function\", \"No protein-level characterization in this study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A hypomorphic Fdft1 allele linking reduced cholesterol biosynthesis to hereditary cataract demonstrated that FDFT1 activity level is physiologically dose-sensitive in vivo.\",\n      \"evidence\": \"Genetic screening and sequencing of mutant rat alleles with functional characterization\",\n      \"pmids\": [\"17460354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between sterol depletion and cataract not resolved\", \"Findings in rat strains, not human\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Loss- and gain-of-function studies recast FDFT1 from a housekeeping enzyme into a tumor suppressor that actively restrains oncogenic AKT/mTOR/HIF1\\u03b1 signaling and glycolysis.\",\n      \"evidence\": \"siRNA knockdown, overexpression, glycolysis assays and xenografts in CRC; miRNA/SREBP-2-axis rescue experiments in CRC, hepatic and ovarian models\",\n      \"pmids\": [\"32313017\", \"32827918\", \"32877662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER sterol enzyme mechanistically suppresses AKT/mTOR not fully resolved at this stage\", \"Relative contribution of cholesterol depletion versus FPP accumulation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Direct small-molecule binding and transcriptional mapping defined how FDFT1 is controlled and how its loss triggers cell death, identifying the TNFR1/NF-\\u03baB/NEDD4 apoptotic axis and SREBP2 as its principal transcriptional driver.\",\n      \"evidence\": \"CETSA/SPR/docking for direct artemisitene binding plus ChIP in breast cancer; RNA-seq, inhibitor (YM-53601) and knockdown in glioblastoma stem cells\",\n      \"pmids\": [\"39461203\", \"39707501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NEDD4 induction depends on cholesterol depletion or direct FDFT1 enzymatic activity not separated\", \"SREBP2 regulation studied in single tumor context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of estrogen-GSK3\\u03b2-LSD1 and microRNA inputs showed FDFT1 transcription is set by hormonal and epigenetic signals, and that its suppression reroutes substrate to non-sterol prenylation to drive chemoresistance.\",\n      \"evidence\": \"CUT&RUN, Co-IP and transcriptomics in chicken theca cells; luciferase, knockdown and pathway gene expression in bladder cancer\",\n      \"pmids\": [\"39595520\", \"39270927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FPP rerouting inferred from pathway gene expression, not direct metabolite flux measurement\", \"Estrogen axis characterized in avian cells only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that bi-allelic somatic silencing of FDFT1 causes porokeratosis provided direct in-human disease evidence that FDFT1-driven cholesterol synthesis is required for normal keratinocyte homeostasis.\",\n      \"evidence\": \"Genomic and bisulfite sequencing, IHC, keratinocyte cholesterol rescue and topical statin treatment\",\n      \"pmids\": [\"38653249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting cholesterol dependence to clonal expansion and cell-cycle change not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistic dissection in HCC and TNBC defined the downstream effector axes and the post-translational control of FDFT1 — the HNF4A/ALDOB/AKT1 axis, AMPK-ULK1 autophagy suppression, and THEM6/HSP90-mediated protection from ERAD.\",\n      \"evidence\": \"Co-IP, promoter binding, metabolite quantification and pharmacological rescue in HCC; ubiquitination assays, protein half-life and ferroptosis readouts in TNBC; autophagosome imaging and AMPK-ULK1 blotting\",\n      \"pmids\": [\"39899681\", \"40931051\", \"42059033\", \"40890513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same axes operate outside liver and breast contexts untested\", \"How cholesterol level mechanistically modulates HNF4A activity not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pharmacological and viral studies extended FDFT1's reach to statin-induced anti-tumor responses, additional non-coding RNA regulation, and modulation of viral replication state through cholesterol.\",\n      \"evidence\": \"AOM/DSS CRC model with atorvastatin; SQS inhibitors in lung cancer; piR-39980 luciferase/knockdown in tongue cancer; METTL7A-SREBP1 Co-IP in CRC; HIV-1 Tat/KSHV expression assays\",\n      \"pmids\": [\"41866501\", \"41089479\", \"40339976\", \"42009961\", \"40947702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KSHV/HIV link rests on expression readouts without biochemical confirmation\", \"Tissue-specificity of the many regulatory inputs not reconciled into one model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether FDFT1's growth-suppressive effects derive primarily from cholesterol/bile-acid depletion, from accumulation of the farnesyl-diphosphate substrate redirected to prenylation, or from a non-catalytic scaffolding role, and how its context-dependent tumor-suppressor versus stemness-promoting functions are reconciled.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of FDFT1 in any signaling complex in the corpus\", \"Direct flux measurements separating sterol from prenylation contributions are lacking\", \"Reconciliation of opposing tumor-context roles unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 5, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"THEM6\", \"HSP90\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}