{"gene":"FDPS","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2019,"finding":"FDPS promotes prostate cancer cell proliferation and colony formation by prenylating small GTPases (RhoA, RhoG, CDC42), which activates downstream AKT and ERK signaling; this oncogenic function is synergistic with PTEN loss. Pharmacological inhibition by zoledronic acid disrupts GTPase prenylation and attenuates AKT/ERK signaling.","method":"Ectopic overexpression and knockdown of FDPS in PCa cells, 3D tumoroids, PTEN conditional knockout mouse model, pharmacological inhibition with zoledronic acid, immunoblot for AKT/ERK signaling, colony formation and proliferation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic OE/KD, pharmacological inhibition, in vivo mouse model, tumoroids) in one study with clear mechanistic pathway placement","pmids":["30914801"],"is_preprint":false},{"year":2021,"finding":"FDPS inhibition (CRISPR/Cas9 or zoledronic acid) radiosensitizes pancreatic ductal adenocarcinoma by attenuating Rac1 and Rho GTPase prenylation, thereby disrupting DNA damage response signaling and activating systemic immune cells.","method":"CRISPR/Cas9 knockout, pharmacological inhibition (zoledronic acid), RNA-Seq of xenografts and patient PBMCs, in vitro cell assays, orthotopic mouse models, patient-derived tumoroids, clinical trial correlates","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO plus pharmacological inhibition, RNA-Seq mechanistic profiling, in vivo orthotopic models, and clinical correlates provide multiple orthogonal lines of evidence","pmids":["34971971"],"is_preprint":false},{"year":2021,"finding":"Cardiac-specific deletion of FDPS leads to cardiac remodeling and dysfunction through accumulation of geranyl pyrophosphate, which causes abnormal prenylation-dependent activation of Ras and Rheb small GTPases, stimulating downstream mTOR and ERK pathways. Farnesyltransferase inhibitor treatment rescued this phenotype.","method":"Cardiac-specific Fdps knockout mice (c-Fdps-/-), echocardiography, histological analysis, immunoblot for Ras/Rheb/mTOR/ERK pathways, farnesyltransferase inhibitor rescue experiment, human cardiomyopathy samples","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO mouse model with defined molecular mechanism, pharmacological rescue, and human tissue validation providing multiple orthogonal methods","pmids":["34467534"],"is_preprint":false},{"year":2017,"finding":"FDPS enzymatic activity is elevated in glioblastoma tumor tissue compared to normal brain; FDPS knockdown in GBM cells (but not normal astrocytes) enhances apoptosis, and FDPS expression correlates with activation of STAT3, ERK, and AKT oncogenic signaling pathways.","method":"FDPS mRNA, protein, and enzyme activity measurement in patient cohort (N=49) and primary derived cells; FDPS silencing in U87 and GBM primary cells vs. normal human astrocytes; apoptosis assays; immunoblot for STAT3/ERK/AKT","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme activity assay combined with genetic silencing and pathway readouts, but mechanistic link between FDPS activity and specific signaling nodes is correlative in this study","pmids":["29075041"],"is_preprint":false},{"year":2020,"finding":"FDPS activates the Wnt/β-catenin signaling pathway in glioma cells, which induces CCL20 expression and promotes macrophage recruitment into the tumor microenvironment; pharmacological macrophage depletion abrogated the oncogenic functions of FDPS.","method":"FDPS overexpression/knockdown in glioma cells, Wnt/β-catenin pathway reporter assays, CCL20 expression analysis, macrophage recruitment assays, pharmacological macrophage depletion","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation with pathway readout and macrophage depletion rescue, single lab, abstract does not detail all controls","pmids":["32596949"],"is_preprint":false},{"year":2013,"finding":"The isoprenoid metabolite iPA (N6-isopentenyladenosine) modulates FDPS enzymatic activity in human NK cells, causing enhanced post-translational prenylation of Ras and other key signaling proteins, which activates MAPK signaling downstream of IL-2R and augments NK cell cytotoxicity and cytokine production.","method":"Ex vivo treatment of human NK cells with iPA, measurement of FDPS activity, flow cytometry for NK activation markers (CD69, CD107a, activating receptors), cytokine secretion assays (CCL5, CCL3, TNF-α, IFN-γ), cytotoxicity assays against tumor targets, MAPK pathway immunoblot","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzyme activity measurement combined with functional NK assays, but mechanistic link relies partly on indirect inference about prenylation","pmids":["23847096"],"is_preprint":false},{"year":2008,"finding":"The human FDPS gene minimal basal promoter contains functional cis-acting elements recognized by Pax5 and OCT-1 transcription factors, which modulate FDPS gene expression; conserved binding sites for NF-Y, SP1, SRE3, and YY1 were also identified.","method":"Deletion mutant analysis of FDPS 5' flanking region, luciferase reporter assays, genomic sequence comparison across species (rat, mouse, dog, chimpanzee, human), transcription factor binding site characterization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional deletion mutant reporter assays with transcription factor identification, single lab, two orthogonal approaches (deletion analysis + binding site characterization)","pmids":["19056481"],"is_preprint":false},{"year":2015,"finding":"Estrogen regulates FDPS expression in the mouse uterus in an estrogen receptor alpha (ERα)-dependent manner; FDPS expression peaks during proestrus, is induced by estrogen in ovariectomized mice, and is suppressed by ERα antagonist ICI 182,780. FDPS contributes to endometrial cancer cell proliferation.","method":"In vivo mouse estrous cycle analysis, ovariectomized mouse model with estrogen treatment and ERα antagonist ICI 182,780 treatment, FDPS expression quantification, histological analysis of human endometrial cancer tissues, functional cell proliferation assays in Ishikawa cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo hormonal manipulation with receptor antagonist rescue, plus cell-line functional assays; single lab, multiple orthogonal methods","pmids":["41683980"],"is_preprint":false},{"year":2023,"finding":"miR-128-3p inhibits chicken intramuscular adipocyte differentiation by directly targeting and downregulating FDPS; luciferase assay confirmed miR-128-3p targets the 3' UTR of FDPS, and functional assays showed FDPS knockdown phenocopies miR-128-3p overexpression in suppressing adipocyte differentiation.","method":"Luciferase 3' UTR reporter assay, miR-128-3p mimic/inhibitor transfection, RNA-seq for DEG identification, functional adipocyte differentiation assays in chicken intramuscular adipocytes","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR luciferase validation plus functional adipogenesis assays, but in chicken (non-mammalian model); consistent with FDPS's role in lipid/isoprenoid metabolism","pmids":["37700222"],"is_preprint":false},{"year":2026,"finding":"FDPS silencing in HCC cells reduced proliferation, migration, invasion, and tumorigenicity and increased apoptosis; phosphoproteomic profiling revealed FDPS depletion causes broad phosphorylation changes in GTPase signaling, protein kinase C activation, glucose metabolism, cytoskeletal remodeling, cell cycle, mTOR (reduced pSer2448), and apoptosis (decreased BCL2, reduced Caspase-9 pSer196, increased cleaved Caspase-3). FDPS inhibitor pamidronate suppressed tumor growth in vivo.","method":"siRNA silencing, lentiviral overexpression, phosphoproteomic profiling, Western blot validation, in vitro proliferation/migration/invasion/apoptosis assays, xenograft mouse models, pamidronate treatment","journal":"Biomolecules & biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomic profiling with Western blot validation plus in vivo xenograft, single lab, multiple orthogonal methods","pmids":["41979127"],"is_preprint":false},{"year":2026,"finding":"FDPS genetic silencing in HCC suppresses tumor cell cholesterol metabolism and proliferation; FDPS inhibition with alendronic acid combined with anti-PD-1 therapy increased lymphoid immune infiltration and enhanced anti-tumor efficacy in orthotopic mouse models.","method":"Genetic silencing, metabolic profiling (intracellular cholesterol levels), orthotopic mouse models, anti-PD-1 combination treatment, immune infiltration analysis, single-cell RNA sequencing, hdWGCNA","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic silencing with metabolic profiling and in vivo orthotopic model; single lab, multiple orthogonal methods","pmids":["41706364"],"is_preprint":false},{"year":2021,"finding":"Novel missense mutations in the FDPS gene (exon 5, c.C535T) were identified in patients with disseminated superficial actinic porokeratosis (DSAP), supporting FDPS's role in the mevalonate pathway underlying epidermal keratinization disorders.","method":"Sanger sequencing of all FDPS exons and flanking introns in patients and unaffected family members; mutation analysis in 100 unrelated control individuals","journal":"Clinica chimica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — sequencing-based mutation identification without functional validation of the specific variant","pmids":["34751146"],"is_preprint":false}],"current_model":"FDPS (farnesyl diphosphate synthase) is a mevalonate pathway enzyme that catalyzes synthesis of farnesyl pyrophosphate (FPP), a key isoprenoid intermediate required for post-translational prenylation of small GTPases (RhoA, RhoG, CDC42, Rac1, Ras, Rheb); through this prenylation activity FDPS controls activation of downstream AKT, ERK, and mTOR signaling pathways, regulates DNA damage responses, modulates immune cell function, and supports cholesterol biosynthesis, with loss-of-function causing accumulation of geranyl pyrophosphate, aberrant GTPase activation, and cardiac or proliferative dysfunction, while its promoter is regulated by Pax5, OCT-1, and estrogen receptor alpha."},"narrative":{"mechanistic_narrative":"FDPS is a mevalonate-pathway enzyme whose synthesis of farnesyl pyrophosphate fuels post-translational prenylation of small GTPases, positioning it as an upstream control point for proliferative, metabolic, and immune signaling [PMID:30914801, PMID:34467534]. Across multiple cancers, FDPS drives oncogenic growth by prenylating Rho-family and Ras-family GTPases (RhoA, RhoG, CDC42, Rac1, Ras, Rheb), thereby activating downstream AKT, ERK, STAT3, and mTOR pathways; this function is targetable with aminobisphosphonate inhibitors such as zoledronic acid, pamidronate, and alendronic acid, which disrupt prenylation, suppress tumor growth, and in pancreatic and hepatocellular models alter the immune microenvironment and synergize with anti-PD-1 therapy [PMID:30914801, PMID:34971971, PMID:29075041, PMID:41979127, PMID:41706364]. In glioma, FDPS additionally engages Wnt/β-catenin signaling to induce CCL20 and recruit tumor-promoting macrophages [PMID:32596949]. The dependence on correct FPP supply is illustrated in the heart, where cardiac-specific FDPS deletion causes accumulation of geranyl pyrophosphate, aberrant Ras/Rheb prenylation, and mTOR/ERK-driven cardiac remodeling that is rescued by farnesyltransferase inhibition [PMID:34467534]. FDPS activity also tunes immune effector function, as the isoprenoid metabolite iPA enhances FDPS-dependent prenylation in NK cells to augment MAPK signaling and cytotoxicity [PMID:23847096]. FDPS expression is controlled by Pax5 and OCT-1 at its basal promoter [PMID:19056481], by estrogen through ERα [PMID:41683980], and post-transcriptionally by miR-128-3p [PMID:37700222].","teleology":[{"year":2008,"claim":"Established how FDPS transcription is controlled by mapping functional cis-elements in its minimal basal promoter, the first step toward understanding its regulated expression.","evidence":"Deletion-mutant luciferase reporter assays and cross-species promoter sequence comparison identifying Pax5, OCT-1, NF-Y, SP1, SRE3, and YY1 sites","pmids":["19056481"],"confidence":"Medium","gaps":["Does not show which factors dominate in specific tissues or disease states","No link between promoter activity and downstream prenylation output"]},{"year":2013,"claim":"Demonstrated that FDPS enzymatic activity is dynamically modulated by an isoprenoid metabolite to shape immune effector function, linking FDPS to prenylation-dependent MAPK signaling beyond housekeeping metabolism.","evidence":"Ex vivo iPA treatment of human NK cells with FDPS activity measurement, NK activation/cytotoxicity assays, and MAPK immunoblot","pmids":["23847096"],"confidence":"Medium","gaps":["Prenylation link partly inferred rather than directly traced to specific GTPase substrates","Mechanism of iPA action on FDPS not structurally defined"]},{"year":2015,"claim":"Showed FDPS expression is hormonally regulated, tying it to estrogen-driven proliferation in reproductive tissue and endometrial cancer.","evidence":"Mouse estrous cycle and ovariectomy/estrogen/ERα-antagonist experiments plus Ishikawa cell proliferation assays","pmids":["41683980"],"confidence":"Medium","gaps":["Whether ERα acts directly at the FDPS promoter not established","Functional contribution of FDPS prenylation in endometrial cells not dissected"]},{"year":2017,"claim":"Connected elevated FDPS enzyme activity to glioblastoma survival, indicating a cancer-cell-selective dependency on FDPS.","evidence":"Enzyme activity and expression profiling in a 49-patient cohort, FDPS silencing in GBM cells versus normal astrocytes, apoptosis assays, and STAT3/ERK/AKT immunoblot","pmids":["29075041"],"confidence":"Medium","gaps":["Link between FDPS activity and signaling nodes is correlative","Specific prenylated effectors not identified in this study"]},{"year":2019,"claim":"Defined the core oncogenic mechanism: FDPS prenylates Rho-family GTPases to activate AKT/ERK, with synergy upon PTEN loss, and is druggable by zoledronic acid.","evidence":"FDPS overexpression/knockdown in prostate cancer cells, 3D tumoroids, PTEN conditional knockout mice, zoledronic acid inhibition, and AKT/ERK immunoblot","pmids":["30914801"],"confidence":"High","gaps":["Direct enzymatic-to-GTPase prenylation step inferred from pathway readouts","Whether other prenyltransferases compensate not addressed"]},{"year":2020,"claim":"Extended FDPS oncogenic signaling to the tumor microenvironment by showing it drives Wnt/β-catenin–dependent CCL20 expression and macrophage recruitment.","evidence":"FDPS gain/loss in glioma cells, Wnt reporter and CCL20 assays, macrophage recruitment assays, and pharmacological macrophage depletion rescue","pmids":["32596949"],"confidence":"Medium","gaps":["Mechanistic link from prenylation to Wnt activation not resolved","Single-lab study without reciprocal in vivo validation of CCL20 axis"]},{"year":2021,"claim":"Showed FDPS inhibition radiosensitizes pancreatic cancer by impairing Rac1/Rho prenylation, disrupting DNA damage response signaling and activating systemic immunity, broadening therapeutic context.","evidence":"CRISPR/Cas9 knockout and zoledronic acid in PDAC, RNA-Seq of xenografts and patient PBMCs, orthotopic models, tumoroids, and clinical correlates","pmids":["34971971"],"confidence":"High","gaps":["Which DNA-damage-response components depend on prenylated GTPases not pinpointed","Systemic immune activation mechanism not fully traced"]},{"year":2021,"claim":"Revealed that proper FDPS function is required to prevent toxic geranyl pyrophosphate accumulation, with cardiac loss causing aberrant Ras/Rheb prenylation and mTOR/ERK-driven cardiomyopathy.","evidence":"Cardiac-specific Fdps knockout mice with echocardiography, histology, Ras/Rheb/mTOR/ERK immunoblot, farnesyltransferase inhibitor rescue, and human cardiomyopathy samples","pmids":["34467534"],"confidence":"High","gaps":["How GPP accumulation mechanistically redirects prenylation not fully defined","Relevance to human cardiomyopathy is associative"]},{"year":2021,"claim":"Linked FDPS coding variants to a human keratinization disorder, implicating FDPS-dependent mevalonate metabolism in epidermal disease.","evidence":"Sanger sequencing of FDPS exons in DSAP patients, family members, and 100 controls identifying c.C535T","pmids":["34751146"],"confidence":"Low","gaps":["No functional validation of the variant's effect on FDPS activity","Causality versus association not established"]},{"year":2023,"claim":"Identified a post-transcriptional regulator of FDPS, showing miR-128-3p directly represses FDPS to control adipocyte differentiation.","evidence":"3'UTR luciferase reporter, miR-128-3p mimic/inhibitor, RNA-seq, and adipocyte differentiation assays in chicken intramuscular adipocytes","pmids":["37700222"],"confidence":"Medium","gaps":["Demonstrated in chicken, not mammalian, model","Downstream prenylation effectors in adipogenesis not identified"]},{"year":2026,"claim":"Provided systems-level confirmation of FDPS signaling reach and its metabolic-immune role in hepatocellular carcinoma, supporting combination with immune checkpoint blockade.","evidence":"FDPS silencing/overexpression in HCC with phosphoproteomics, cholesterol metabolic profiling, xenograft and orthotopic models, pamidronate and alendronic acid plus anti-PD-1 treatment, and single-cell RNA-seq","pmids":["41979127","41706364"],"confidence":"Medium","gaps":["Phosphoproteomic changes are broad and not all causally attributed to specific GTPases","Direct mechanism of immune infiltration enhancement not isolated"]},{"year":null,"claim":"It remains unresolved how FDPS-generated FPP supply is selectively partitioned among individual GTPase substrates to produce the distinct AKT, ERK, STAT3, mTOR, and Wnt outputs observed across tissues.","evidence":"No single study in the corpus traces flux from FDPS catalysis to a defined prenylation substrate and a unique signaling output","pmids":[],"confidence":"Low","gaps":["No substrate-resolved prenylation quantification","No structural basis for context-specific FPP allocation","Compensation by alternative isoprenoid routes unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3,5]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5,10]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14324","full_name":"Farnesyl pyrophosphate synthase","aliases":["(2E,6E)-farnesyl diphosphate synthase","Dimethylallyltranstransferase","Farnesyl diphosphate synthase","Geranyltranstransferase"],"length_aa":419,"mass_kda":48.3,"function":"Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P14324/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/FDPS","classification":"Common Essential","n_dependent_lines":949,"n_total_lines":1208,"dependency_fraction":0.7855960264900662},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000160752","cell_line_id":"CID000278","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"DHCR24","stoichiometry":0.2},{"gene":"NUP88","stoichiometry":0.2},{"gene":"PPP1R9B","stoichiometry":0.2},{"gene":"PKM","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"ENO1","stoichiometry":0.2},{"gene":"PFN1","stoichiometry":0.2},{"gene":"DFFA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000278","total_profiled":1310},"omim":[{"mim_id":"619682","title":"ALL-TRANS RETINOIC ACID-INDUCED DIFFERENTIATION FACTOR; ATRAID","url":"https://www.omim.org/entry/619682"},{"mim_id":"619137","title":"SOLUTE CARRIER FAMILY 37, MEMBER A3; SLC37A3","url":"https://www.omim.org/entry/619137"},{"mim_id":"616631","title":"POROKERATOSIS 9, MULTIPLE TYPES; POROK9","url":"https://www.omim.org/entry/616631"},{"mim_id":"175800","title":"POROKERATOSIS 1, MULTIPLE TYPES; POROK1","url":"https://www.omim.org/entry/175800"},{"mim_id":"134629","title":"FARNESYL DIPHOSPHATE SYNTHASE; FDPS","url":"https://www.omim.org/entry/134629"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":332.6}],"url":"https://www.proteinatlas.org/search/FDPS"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P14324","domains":[{"cath_id":"1.10.600.10","chopping":"75-413","consensus_level":"medium","plddt":96.5175,"start":75,"end":413}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14324","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14324-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14324-F1-predicted_aligned_error_v6.png","plddt_mean":85.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FDPS","jax_strain_url":"https://www.jax.org/strain/search?query=FDPS"},"sequence":{"accession":"P14324","fasta_url":"https://rest.uniprot.org/uniprotkb/P14324.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14324/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14324"}},"corpus_meta":[{"pmid":"30914801","id":"PMC_30914801","title":"FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30914801","citation_count":52,"is_preprint":false},{"pmid":"29075041","id":"PMC_29075041","title":"Deregulated expression and activity of Farnesyl Diphosphate Synthase (FDPS) in Glioblastoma.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29075041","citation_count":46,"is_preprint":false},{"pmid":"18687167","id":"PMC_18687167","title":"Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis.","date":"2008","source":"Current medical research and opinion","url":"https://pubmed.ncbi.nlm.nih.gov/18687167","citation_count":37,"is_preprint":false},{"pmid":"32596949","id":"PMC_32596949","title":"FDPS promotes glioma growth and macrophage recruitment by regulating CCL20 via Wnt/β-catenin signalling pathway.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32596949","citation_count":29,"is_preprint":false},{"pmid":"34971971","id":"PMC_34971971","title":"Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling.","date":"2021","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34971971","citation_count":29,"is_preprint":false},{"pmid":"23847096","id":"PMC_23847096","title":"N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation.","date":"2013","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/23847096","citation_count":24,"is_preprint":false},{"pmid":"19056481","id":"PMC_19056481","title":"Characterization and functional analysis of cis-acting elements of the human farnesyl diphosphate synthetase (FDPS) gene 5' flanking region.","date":"2008","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19056481","citation_count":21,"is_preprint":false},{"pmid":"37700222","id":"PMC_37700222","title":"miR-128-3p inhibits intramuscular adipocytes differentiation in chickens by downregulating FDPS.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37700222","citation_count":17,"is_preprint":false},{"pmid":"23839109","id":"PMC_23839109","title":"The NF-κB pathway: regulation of the instability of atherosclerotic plaques activated by Fg, Fb, and FDPs.","date":"2013","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23839109","citation_count":14,"is_preprint":false},{"pmid":"31774873","id":"PMC_31774873","title":"Polymorphisms of FDPS, LRP5, SOST and VKORC1 genes and their relation with osteoporosis in postmenopausal Romanian women.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31774873","citation_count":12,"is_preprint":false},{"pmid":"34467534","id":"PMC_34467534","title":"Cardiac-specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP-binding proteins.","date":"2021","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34467534","citation_count":10,"is_preprint":false},{"pmid":"34751146","id":"PMC_34751146","title":"Novel missense mutations of MVK and FDPS gene in Chinese patients with disseminated superficial actinic porokeratosis.","date":"2021","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34751146","citation_count":5,"is_preprint":false},{"pmid":"22338925","id":"PMC_22338925","title":"Effects of differences in polymorphism of gene encoding enzyme faenesyl diphosphate synthase (FDPS), rs2297480, on bone mineral density and biochemical markers of bone turnover in Thai postmenopausal women.","date":"2011","source":"Journal of the Medical Association of Thailand = Chotmaihet thangphaet","url":"https://pubmed.ncbi.nlm.nih.gov/22338925","citation_count":4,"is_preprint":false},{"pmid":"41706364","id":"PMC_41706364","title":"Single-cell mapping of cholesterol metabolism reveals FDPS as a therapeutic vulnerability in hepatocellular carcinoma.","date":"2026","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/41706364","citation_count":0,"is_preprint":false},{"pmid":"41683980","id":"PMC_41683980","title":"Estrogen-Dependent Regulation of FDPS in the Mouse Uterus and Its Expression in Endometrial Cancer.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41683980","citation_count":0,"is_preprint":false},{"pmid":"41689836","id":"PMC_41689836","title":"The association between single-nucleotide polymorphisms of FDPS Rs2297480 and MECP2 Rs2734647 genes and the susceptibility to rheumatoid arthritis in Egyptian patients.","date":"2026","source":"Journal of immunoassay & immunochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41689836","citation_count":0,"is_preprint":false},{"pmid":"41979127","id":"PMC_41979127","title":"FDPS links tumor progression, phosphoproteomic reprogramming, and therapeutic vulnerability in hepatocellular carcinoma.","date":"2026","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41979127","citation_count":0,"is_preprint":false},{"pmid":"41737384","id":"PMC_41737384","title":"Identification of two novel MVD mutations and one novel FDPS mutation in Chinese patients with porokeratosis.","date":"2026","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41737384","citation_count":0,"is_preprint":false},{"pmid":"41737382","id":"PMC_41737382","title":"Correction: Identification of two novel MVD mutations and one novel FDPS mutation in Chinese patients with porokeratosis.","date":"2026","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41737382","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11417,"output_tokens":3297,"usd":0.041853,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10976,"output_tokens":3837,"usd":0.075402,"stage2_stop_reason":"end_turn"},"total_usd":0.117255,"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\": 2019,\n      \"finding\": \"FDPS promotes prostate cancer cell proliferation and colony formation by prenylating small GTPases (RhoA, RhoG, CDC42), which activates downstream AKT and ERK signaling; this oncogenic function is synergistic with PTEN loss. Pharmacological inhibition by zoledronic acid disrupts GTPase prenylation and attenuates AKT/ERK signaling.\",\n      \"method\": \"Ectopic overexpression and knockdown of FDPS in PCa cells, 3D tumoroids, PTEN conditional knockout mouse model, pharmacological inhibition with zoledronic acid, immunoblot for AKT/ERK signaling, colony formation and proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic OE/KD, pharmacological inhibition, in vivo mouse model, tumoroids) in one study with clear mechanistic pathway placement\",\n      \"pmids\": [\"30914801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FDPS inhibition (CRISPR/Cas9 or zoledronic acid) radiosensitizes pancreatic ductal adenocarcinoma by attenuating Rac1 and Rho GTPase prenylation, thereby disrupting DNA damage response signaling and activating systemic immune cells.\",\n      \"method\": \"CRISPR/Cas9 knockout, pharmacological inhibition (zoledronic acid), RNA-Seq of xenografts and patient PBMCs, in vitro cell assays, orthotopic mouse models, patient-derived tumoroids, clinical trial correlates\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO plus pharmacological inhibition, RNA-Seq mechanistic profiling, in vivo orthotopic models, and clinical correlates provide multiple orthogonal lines of evidence\",\n      \"pmids\": [\"34971971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cardiac-specific deletion of FDPS leads to cardiac remodeling and dysfunction through accumulation of geranyl pyrophosphate, which causes abnormal prenylation-dependent activation of Ras and Rheb small GTPases, stimulating downstream mTOR and ERK pathways. Farnesyltransferase inhibitor treatment rescued this phenotype.\",\n      \"method\": \"Cardiac-specific Fdps knockout mice (c-Fdps-/-), echocardiography, histological analysis, immunoblot for Ras/Rheb/mTOR/ERK pathways, farnesyltransferase inhibitor rescue experiment, human cardiomyopathy samples\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO mouse model with defined molecular mechanism, pharmacological rescue, and human tissue validation providing multiple orthogonal methods\",\n      \"pmids\": [\"34467534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FDPS enzymatic activity is elevated in glioblastoma tumor tissue compared to normal brain; FDPS knockdown in GBM cells (but not normal astrocytes) enhances apoptosis, and FDPS expression correlates with activation of STAT3, ERK, and AKT oncogenic signaling pathways.\",\n      \"method\": \"FDPS mRNA, protein, and enzyme activity measurement in patient cohort (N=49) and primary derived cells; FDPS silencing in U87 and GBM primary cells vs. normal human astrocytes; apoptosis assays; immunoblot for STAT3/ERK/AKT\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme activity assay combined with genetic silencing and pathway readouts, but mechanistic link between FDPS activity and specific signaling nodes is correlative in this study\",\n      \"pmids\": [\"29075041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FDPS activates the Wnt/β-catenin signaling pathway in glioma cells, which induces CCL20 expression and promotes macrophage recruitment into the tumor microenvironment; pharmacological macrophage depletion abrogated the oncogenic functions of FDPS.\",\n      \"method\": \"FDPS overexpression/knockdown in glioma cells, Wnt/β-catenin pathway reporter assays, CCL20 expression analysis, macrophage recruitment assays, pharmacological macrophage depletion\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation with pathway readout and macrophage depletion rescue, single lab, abstract does not detail all controls\",\n      \"pmids\": [\"32596949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The isoprenoid metabolite iPA (N6-isopentenyladenosine) modulates FDPS enzymatic activity in human NK cells, causing enhanced post-translational prenylation of Ras and other key signaling proteins, which activates MAPK signaling downstream of IL-2R and augments NK cell cytotoxicity and cytokine production.\",\n      \"method\": \"Ex vivo treatment of human NK cells with iPA, measurement of FDPS activity, flow cytometry for NK activation markers (CD69, CD107a, activating receptors), cytokine secretion assays (CCL5, CCL3, TNF-α, IFN-γ), cytotoxicity assays against tumor targets, MAPK pathway immunoblot\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzyme activity measurement combined with functional NK assays, but mechanistic link relies partly on indirect inference about prenylation\",\n      \"pmids\": [\"23847096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The human FDPS gene minimal basal promoter contains functional cis-acting elements recognized by Pax5 and OCT-1 transcription factors, which modulate FDPS gene expression; conserved binding sites for NF-Y, SP1, SRE3, and YY1 were also identified.\",\n      \"method\": \"Deletion mutant analysis of FDPS 5' flanking region, luciferase reporter assays, genomic sequence comparison across species (rat, mouse, dog, chimpanzee, human), transcription factor binding site characterization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional deletion mutant reporter assays with transcription factor identification, single lab, two orthogonal approaches (deletion analysis + binding site characterization)\",\n      \"pmids\": [\"19056481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Estrogen regulates FDPS expression in the mouse uterus in an estrogen receptor alpha (ERα)-dependent manner; FDPS expression peaks during proestrus, is induced by estrogen in ovariectomized mice, and is suppressed by ERα antagonist ICI 182,780. FDPS contributes to endometrial cancer cell proliferation.\",\n      \"method\": \"In vivo mouse estrous cycle analysis, ovariectomized mouse model with estrogen treatment and ERα antagonist ICI 182,780 treatment, FDPS expression quantification, histological analysis of human endometrial cancer tissues, functional cell proliferation assays in Ishikawa cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo hormonal manipulation with receptor antagonist rescue, plus cell-line functional assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41683980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-128-3p inhibits chicken intramuscular adipocyte differentiation by directly targeting and downregulating FDPS; luciferase assay confirmed miR-128-3p targets the 3' UTR of FDPS, and functional assays showed FDPS knockdown phenocopies miR-128-3p overexpression in suppressing adipocyte differentiation.\",\n      \"method\": \"Luciferase 3' UTR reporter assay, miR-128-3p mimic/inhibitor transfection, RNA-seq for DEG identification, functional adipocyte differentiation assays in chicken intramuscular adipocytes\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR luciferase validation plus functional adipogenesis assays, but in chicken (non-mammalian model); consistent with FDPS's role in lipid/isoprenoid metabolism\",\n      \"pmids\": [\"37700222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FDPS silencing in HCC cells reduced proliferation, migration, invasion, and tumorigenicity and increased apoptosis; phosphoproteomic profiling revealed FDPS depletion causes broad phosphorylation changes in GTPase signaling, protein kinase C activation, glucose metabolism, cytoskeletal remodeling, cell cycle, mTOR (reduced pSer2448), and apoptosis (decreased BCL2, reduced Caspase-9 pSer196, increased cleaved Caspase-3). FDPS inhibitor pamidronate suppressed tumor growth in vivo.\",\n      \"method\": \"siRNA silencing, lentiviral overexpression, phosphoproteomic profiling, Western blot validation, in vitro proliferation/migration/invasion/apoptosis assays, xenograft mouse models, pamidronate treatment\",\n      \"journal\": \"Biomolecules & biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomic profiling with Western blot validation plus in vivo xenograft, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41979127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FDPS genetic silencing in HCC suppresses tumor cell cholesterol metabolism and proliferation; FDPS inhibition with alendronic acid combined with anti-PD-1 therapy increased lymphoid immune infiltration and enhanced anti-tumor efficacy in orthotopic mouse models.\",\n      \"method\": \"Genetic silencing, metabolic profiling (intracellular cholesterol levels), orthotopic mouse models, anti-PD-1 combination treatment, immune infiltration analysis, single-cell RNA sequencing, hdWGCNA\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic silencing with metabolic profiling and in vivo orthotopic model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41706364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Novel missense mutations in the FDPS gene (exon 5, c.C535T) were identified in patients with disseminated superficial actinic porokeratosis (DSAP), supporting FDPS's role in the mevalonate pathway underlying epidermal keratinization disorders.\",\n      \"method\": \"Sanger sequencing of all FDPS exons and flanking introns in patients and unaffected family members; mutation analysis in 100 unrelated control individuals\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — sequencing-based mutation identification without functional validation of the specific variant\",\n      \"pmids\": [\"34751146\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FDPS (farnesyl diphosphate synthase) is a mevalonate pathway enzyme that catalyzes synthesis of farnesyl pyrophosphate (FPP), a key isoprenoid intermediate required for post-translational prenylation of small GTPases (RhoA, RhoG, CDC42, Rac1, Ras, Rheb); through this prenylation activity FDPS controls activation of downstream AKT, ERK, and mTOR signaling pathways, regulates DNA damage responses, modulates immune cell function, and supports cholesterol biosynthesis, with loss-of-function causing accumulation of geranyl pyrophosphate, aberrant GTPase activation, and cardiac or proliferative dysfunction, while its promoter is regulated by Pax5, OCT-1, and estrogen receptor alpha.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FDPS is a mevalonate-pathway enzyme whose synthesis of farnesyl pyrophosphate fuels post-translational prenylation of small GTPases, positioning it as an upstream control point for proliferative, metabolic, and immune signaling [#0, #2]. Across multiple cancers, FDPS drives oncogenic growth by prenylating Rho-family and Ras-family GTPases (RhoA, RhoG, CDC42, Rac1, Ras, Rheb), thereby activating downstream AKT, ERK, STAT3, and mTOR pathways; this function is targetable with aminobisphosphonate inhibitors such as zoledronic acid, pamidronate, and alendronic acid, which disrupt prenylation, suppress tumor growth, and in pancreatic and hepatocellular models alter the immune microenvironment and synergize with anti-PD-1 therapy [#0, #1, #3, #9, #10]. In glioma, FDPS additionally engages Wnt/\\u03b2-catenin signaling to induce CCL20 and recruit tumor-promoting macrophages [#4]. The dependence on correct FPP supply is illustrated in the heart, where cardiac-specific FDPS deletion causes accumulation of geranyl pyrophosphate, aberrant Ras/Rheb prenylation, and mTOR/ERK-driven cardiac remodeling that is rescued by farnesyltransferase inhibition [#2]. FDPS activity also tunes immune effector function, as the isoprenoid metabolite iPA enhances FDPS-dependent prenylation in NK cells to augment MAPK signaling and cytotoxicity [#5]. FDPS expression is controlled by Pax5 and OCT-1 at its basal promoter [#6], by estrogen through ER\\u03b1 [#7], and post-transcriptionally by miR-128-3p [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established how FDPS transcription is controlled by mapping functional cis-elements in its minimal basal promoter, the first step toward understanding its regulated expression.\",\n      \"evidence\": \"Deletion-mutant luciferase reporter assays and cross-species promoter sequence comparison identifying Pax5, OCT-1, NF-Y, SP1, SRE3, and YY1 sites\",\n      \"pmids\": [\"19056481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not show which factors dominate in specific tissues or disease states\", \"No link between promoter activity and downstream prenylation output\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that FDPS enzymatic activity is dynamically modulated by an isoprenoid metabolite to shape immune effector function, linking FDPS to prenylation-dependent MAPK signaling beyond housekeeping metabolism.\",\n      \"evidence\": \"Ex vivo iPA treatment of human NK cells with FDPS activity measurement, NK activation/cytotoxicity assays, and MAPK immunoblot\",\n      \"pmids\": [\"23847096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Prenylation link partly inferred rather than directly traced to specific GTPase substrates\", \"Mechanism of iPA action on FDPS not structurally defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed FDPS expression is hormonally regulated, tying it to estrogen-driven proliferation in reproductive tissue and endometrial cancer.\",\n      \"evidence\": \"Mouse estrous cycle and ovariectomy/estrogen/ER\\u03b1-antagonist experiments plus Ishikawa cell proliferation assays\",\n      \"pmids\": [\"41683980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER\\u03b1 acts directly at the FDPS promoter not established\", \"Functional contribution of FDPS prenylation in endometrial cells not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected elevated FDPS enzyme activity to glioblastoma survival, indicating a cancer-cell-selective dependency on FDPS.\",\n      \"evidence\": \"Enzyme activity and expression profiling in a 49-patient cohort, FDPS silencing in GBM cells versus normal astrocytes, apoptosis assays, and STAT3/ERK/AKT immunoblot\",\n      \"pmids\": [\"29075041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between FDPS activity and signaling nodes is correlative\", \"Specific prenylated effectors not identified in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the core oncogenic mechanism: FDPS prenylates Rho-family GTPases to activate AKT/ERK, with synergy upon PTEN loss, and is druggable by zoledronic acid.\",\n      \"evidence\": \"FDPS overexpression/knockdown in prostate cancer cells, 3D tumoroids, PTEN conditional knockout mice, zoledronic acid inhibition, and AKT/ERK immunoblot\",\n      \"pmids\": [\"30914801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic-to-GTPase prenylation step inferred from pathway readouts\", \"Whether other prenyltransferases compensate not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended FDPS oncogenic signaling to the tumor microenvironment by showing it drives Wnt/\\u03b2-catenin\\u2013dependent CCL20 expression and macrophage recruitment.\",\n      \"evidence\": \"FDPS gain/loss in glioma cells, Wnt reporter and CCL20 assays, macrophage recruitment assays, and pharmacological macrophage depletion rescue\",\n      \"pmids\": [\"32596949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from prenylation to Wnt activation not resolved\", \"Single-lab study without reciprocal in vivo validation of CCL20 axis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed FDPS inhibition radiosensitizes pancreatic cancer by impairing Rac1/Rho prenylation, disrupting DNA damage response signaling and activating systemic immunity, broadening therapeutic context.\",\n      \"evidence\": \"CRISPR/Cas9 knockout and zoledronic acid in PDAC, RNA-Seq of xenografts and patient PBMCs, orthotopic models, tumoroids, and clinical correlates\",\n      \"pmids\": [\"34971971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which DNA-damage-response components depend on prenylated GTPases not pinpointed\", \"Systemic immune activation mechanism not fully traced\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed that proper FDPS function is required to prevent toxic geranyl pyrophosphate accumulation, with cardiac loss causing aberrant Ras/Rheb prenylation and mTOR/ERK-driven cardiomyopathy.\",\n      \"evidence\": \"Cardiac-specific Fdps knockout mice with echocardiography, histology, Ras/Rheb/mTOR/ERK immunoblot, farnesyltransferase inhibitor rescue, and human cardiomyopathy samples\",\n      \"pmids\": [\"34467534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GPP accumulation mechanistically redirects prenylation not fully defined\", \"Relevance to human cardiomyopathy is associative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked FDPS coding variants to a human keratinization disorder, implicating FDPS-dependent mevalonate metabolism in epidermal disease.\",\n      \"evidence\": \"Sanger sequencing of FDPS exons in DSAP patients, family members, and 100 controls identifying c.C535T\",\n      \"pmids\": [\"34751146\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of the variant's effect on FDPS activity\", \"Causality versus association not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a post-transcriptional regulator of FDPS, showing miR-128-3p directly represses FDPS to control adipocyte differentiation.\",\n      \"evidence\": \"3'UTR luciferase reporter, miR-128-3p mimic/inhibitor, RNA-seq, and adipocyte differentiation assays in chicken intramuscular adipocytes\",\n      \"pmids\": [\"37700222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in chicken, not mammalian, model\", \"Downstream prenylation effectors in adipogenesis not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided systems-level confirmation of FDPS signaling reach and its metabolic-immune role in hepatocellular carcinoma, supporting combination with immune checkpoint blockade.\",\n      \"evidence\": \"FDPS silencing/overexpression in HCC with phosphoproteomics, cholesterol metabolic profiling, xenograft and orthotopic models, pamidronate and alendronic acid plus anti-PD-1 treatment, and single-cell RNA-seq\",\n      \"pmids\": [\"41979127\", \"41706364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphoproteomic changes are broad and not all causally attributed to specific GTPases\", \"Direct mechanism of immune infiltration enhancement not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how FDPS-generated FPP supply is selectively partitioned among individual GTPase substrates to produce the distinct AKT, ERK, STAT3, mTOR, and Wnt outputs observed across tissues.\",\n      \"evidence\": \"No single study in the corpus traces flux from FDPS catalysis to a defined prenylation substrate and a unique signaling output\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No substrate-resolved prenylation quantification\", \"No structural basis for context-specific FPP allocation\", \"Compensation by alternative isoprenoid routes unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}