{"gene":"ELOVL7","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"ELOVL7 encodes a long-chain fatty acid elongase that preferentially elongates saturated very-long-chain fatty acids (SVLCFAs, C20:0 and longer), as demonstrated by in vitro fatty acid elongation assay and fatty acid composition analysis in prostate cancer cells.","method":"In vitro fatty acid elongation assay; fatty acid composition analysis (lipidomics); siRNA knockdown with lipid profiling","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay combined with fatty acid composition analysis and knockdown, single lab but multiple orthogonal methods","pmids":["19826053"],"is_preprint":false},{"year":2009,"finding":"ELOVL7 expression is transcriptionally regulated by the androgen pathway through the transcription factor SREBP1, similarly to other lipogenic enzymes in prostate cancer cells.","method":"Genome-wide gene expression analysis; pathway analysis linking androgen signaling to SREBP1-mediated ELOVL7 transcription in clinical prostate cancer samples","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — expression analysis with pathway linkage in clinical samples, single lab, mechanistic detail limited in abstract","pmids":["19826053"],"is_preprint":false},{"year":2009,"finding":"Knockdown of ELOVL7 in prostate cancer cells reduced saturated very-long-chain fatty acids (SVLCFAs) in phospholipids and neutral lipids (including cholesterol ester), and attenuated de novo androgen synthesis, demonstrating a functional link between ELOVL7-mediated SVLCFA elongation and steroidogenesis.","method":"siRNA knockdown; lipid profiling of phospholipids and neutral lipids; de novo androgen synthesis assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined lipid and steroidogenesis phenotype, single lab, multiple complementary readouts","pmids":["19826053"],"is_preprint":false},{"year":2019,"finding":"In goat mammary epithelial cells, ELOVL7 overexpression increased the elongation index of C16:1 (palmitoleic acid) and altered concentrations of vaccenic acid (C18:1n7) and linoleic acid (C18:2), while overexpression decreased palmitoleic and oleic acid concentrations, indicating ELOVL7 preferentially elongates unsaturated C16–C18 fatty acids in this cell type.","method":"Overexpression and knockdown of ELOVL7 in goat mammary epithelial cells (GMEC); fatty acid composition analysis; elongation index calculation","journal":"Animals : an open access journal from MDPI","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with fatty acid profiling, single lab, two orthogonal perturbations","pmids":["31242694"],"is_preprint":false},{"year":2023,"finding":"ELOVL7 is upregulated in THP-1-derived M1-like macrophages via an NF-κB-dependent (not STAT1-dependent) transcriptional mechanism, and ELOVL7 knockdown decreases IL-6 and IL-12/IL-23 p40 production, placing ELOVL7 downstream of NF-κB signaling in the pro-inflammatory macrophage response.","method":"RNA-seq; NF-κB inhibitor (BAY11-7082) and STAT1 inhibitor (fludarabine) treatment; siRNA knockdown; cytokine ELISA; Metascape/GO enrichment analysis","journal":"Journal of clinical biochemistry and nutrition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor epistasis plus KD with cytokine readout, single lab, multiple orthogonal methods","pmids":["37251958"],"is_preprint":false},{"year":2023,"finding":"ELOVL7 is upregulated in plasmacytoid dendritic cells (pDCs) treated with TLR7 and TLR9 agonists, suggesting ELOVL7 expression is induced downstream of innate immune receptor signaling in pDCs.","method":"RNA-seq of pDCs stimulated with TLR7/TLR9 agonists","journal":"Journal of clinical biochemistry and nutrition","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RNA-seq observation in pDCs, no functional follow-up reported in abstract","pmids":["37251958"],"is_preprint":false},{"year":2025,"finding":"Upregulation of Elovl7 in injured podocytes leads to accumulation of phospholipids with long-chain polyunsaturated fatty acyl (LC-PUFA) tails, increasing lipid peroxidation and sensitizing podocytes to ferroptosis; this was confirmed by podocyte-specific Elovl7 knockout mice and Elovl7 knockdown podocyte cell lines.","method":"snRNA-seq; targeted lipidomics; podocyte-specific Elovl7 knockout mouse model; siRNA knockdown in podocyte cell line; ferroptosis scoring","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO plus in vitro KD, lipidomics, and functional ferroptosis readout; multiple orthogonal methods across cell and animal models","pmids":["41285716"],"is_preprint":false},{"year":2025,"finding":"In cardiac hypertrophy, fumarate hydratase (FH) suppresses ELOVL7 transcription via the SREBP transcription factor (malate-SREBP-Elovl7 axis); overexpression of Elovl7 reverses the cardioprotective effects of FH overexpression, establishing Elovl7 as a downstream effector of SREBP in pathological cardiac lipid remodeling.","method":"AAV9-mediated cardiomyocyte-specific FH overexpression; TAC mouse model; RNA sequencing; untargeted metabolomics; Elovl7 overexpression rescue experiment; SREBP knockdown","journal":"Acta pharmacologica Sinica","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (SREBP KD → Elovl7 reduction; Elovl7 OE reverses FH protection) with transcriptomics and metabolomics, single lab but multiple orthogonal approaches","pmids":["40940503"],"is_preprint":false}],"current_model":"ELOVL7 is a very-long-chain fatty acid elongase whose transcription is driven by SREBP (downstream of androgen signaling in prostate cancer and upstream of cardiac remodeling), and whose enzymatic activity elongates saturated VLCFAs (C20+) in prostate cells and unsaturated C16–C18 fatty acids in other contexts; accumulation of LC-PUFA-containing phospholipids via ELOVL7 sensitizes podocytes to ferroptosis, while in macrophages NF-κB-dependent ELOVL7 upregulation promotes IL-6 and IL-12/p40 production, collectively placing ELOVL7 at the intersection of lipid metabolism, inflammatory signaling, and cell death regulation."},"narrative":{"mechanistic_narrative":"ELOVL7 is a very-long-chain fatty acid elongase that sits at the intersection of lipid metabolism, SREBP-driven transcriptional programs, and inflammatory and cell-death signaling [PMID:19826053, PMID:41285716, PMID:40940503]. Its core biochemical activity is the elongation of fatty acids: in prostate cancer cells it preferentially elongates saturated very-long-chain fatty acids (C20:0 and longer), and its knockdown reduces these species in both phospholipids and neutral lipids while attenuating de novo androgen synthesis, linking ELOVL7 elongation to steroidogenesis [PMID:19826053]. Substrate preference is context-dependent: in goat mammary epithelial cells ELOVL7 instead acts on unsaturated C16–C18 fatty acids [PMID:31242694]. Transcriptionally, ELOVL7 is a downstream effector of SREBP — induced by androgen signaling via SREBP1 in prostate cancer [PMID:19826053], and repressed through a malate–SREBP axis by fumarate hydratase in cardiac hypertrophy, where forced ELOVL7 expression reverses the cardioprotective effect of FH [PMID:40940503]. In injured podocytes, ELOVL7 upregulation drives accumulation of phospholipids bearing long-chain polyunsaturated acyl tails, raising lipid peroxidation and sensitizing cells to ferroptosis, as confirmed by podocyte-specific knockout mice [PMID:41285716]. In macrophages, NF-κB-dependent ELOVL7 induction promotes IL-6 and IL-12/IL-23 p40 production, placing the enzyme within the pro-inflammatory response [PMID:37251958].","teleology":[{"year":2009,"claim":"Established the fundamental biochemical identity of ELOVL7 as an elongase with a defined substrate preference, and connected its lipid output to a physiological process (steroidogenesis) in prostate cancer.","evidence":"In vitro fatty acid elongation assay, lipidomic fatty acid composition analysis, and siRNA knockdown with androgen synthesis readout in prostate cancer cells","pmids":["19826053"],"confidence":"High","gaps":["No structural model of the elongase or catalytic mechanism","Substrate-selectivity determinants for C20+ saturated VLCFAs not defined","SREBP1 regulation inferred from expression/pathway analysis rather than direct promoter occupancy"]},{"year":2019,"claim":"Showed that ELOVL7 substrate preference is tissue-dependent, elongating unsaturated C16–C18 species in mammary epithelium rather than the saturated VLCFAs seen in prostate cells.","evidence":"Overexpression and knockdown in goat mammary epithelial cells with fatty acid profiling and elongation index calculation","pmids":["31242694"],"confidence":"Medium","gaps":["Mechanism dictating saturated vs unsaturated substrate selection unknown","Cross-species relevance to human ELOVL7 not established"]},{"year":2023,"claim":"Placed ELOVL7 within innate immune and inflammatory signaling by defining the transcriptional input (NF-κB, not STAT1) and a functional cytokine output in macrophages.","evidence":"RNA-seq, NF-κB/STAT1 pharmacological inhibitor epistasis, siRNA knockdown, and cytokine ELISA in THP-1-derived macrophages; RNA-seq of TLR7/9-stimulated pDCs","pmids":["37251958"],"confidence":"Medium","gaps":["Which lipid product mediates the cytokine effect is unresolved","pDC induction is a single RNA-seq observation without functional follow-up","Direct NF-κB binding to the ELOVL7 locus not shown"]},{"year":2025,"claim":"Linked ELOVL7 elongase activity to a specific cell-death mechanism, showing its LC-PUFA-phospholipid output sensitizes podocytes to ferroptosis in vivo.","evidence":"snRNA-seq, targeted lipidomics, podocyte-specific Elovl7 knockout mice, knockdown cell lines, and ferroptosis scoring","pmids":["41285716"],"confidence":"High","gaps":["Whether the same ferroptosis-sensitizing role operates in non-podocyte tissues is untested","Coupling between ELOVL7 product and peroxidation machinery not mechanistically dissected"]},{"year":2025,"claim":"Defined ELOVL7 as a downstream effector node of a metabolite-controlled SREBP axis in pathological cardiac remodeling, with causal rescue establishing directionality.","evidence":"Cardiomyocyte-specific FH overexpression (AAV9), TAC model, RNA-seq, metabolomics, SREBP knockdown, and Elovl7 overexpression rescue in mice","pmids":["40940503"],"confidence":"High","gaps":["Which ELOVL7 lipid products drive cardiac hypertrophy not identified","Mechanism by which malate/FH modulates SREBP activity toward ELOVL7 not fully resolved"]},{"year":null,"claim":"How a single elongase's product spectrum is redirected across tissues (saturated VLCFA vs LC-PUFA vs unsaturated C16–C18) to produce divergent outcomes — steroidogenesis, ferroptosis, inflammation, cardiac remodeling — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking substrate selection to downstream phenotype","No structural or regulatory basis for context-dependent specificity"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A1L3X0","full_name":"Very long chain fatty acid elongase 7","aliases":["3-keto acyl-CoA synthase ELOVL7","ELOVL fatty acid elongase 7","ELOVL FA elongase 7","Elongation of very long chain fatty acids protein 7","Very long chain 3-ketoacyl-CoA synthase 7","Very long chain 3-oxoacyl-CoA synthase 7"],"length_aa":281,"mass_kda":33.4,"function":"Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme with higher activity toward C18 acyl-CoAs, especially C18:3(n-3) acyl-CoAs and C18:3(n-6)-CoAs. Also active toward C20:4-, C18:0-, C18:1-, C18:2- and C16:0-CoAs, and weakly toward C20:0-CoA. Little or no activity toward C22:0-, C24:0-, or C26:0-CoAs. May participate in the production of saturated and polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/A1L3X0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELOVL7","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ELOVL7","total_profiled":1310},"omim":[{"mim_id":"614451","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 7; ELOVL7","url":"https://www.omim.org/entry/614451"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ELOVL7"},"hgnc":{"alias_symbol":["FLJ23563"],"prev_symbol":[]},"alphafold":{"accession":"A1L3X0","domains":[{"cath_id":"-","chopping":"32-53_63-226_233-263","consensus_level":"high","plddt":93.2941,"start":32,"end":263}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A1L3X0","model_url":"https://alphafold.ebi.ac.uk/files/AF-A1L3X0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A1L3X0-F1-predicted_aligned_error_v6.png","plddt_mean":89.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELOVL7","jax_strain_url":"https://www.jax.org/strain/search?query=ELOVL7"},"sequence":{"accession":"A1L3X0","fasta_url":"https://rest.uniprot.org/uniprotkb/A1L3X0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A1L3X0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A1L3X0"}},"corpus_meta":[{"pmid":"19826053","id":"PMC_19826053","title":"Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19826053","citation_count":165,"is_preprint":false},{"pmid":"19525295","id":"PMC_19525295","title":"Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19525295","citation_count":32,"is_preprint":false},{"pmid":"33750834","id":"PMC_33750834","title":"Omics data integration identifies ELOVL7 and MMD gene regions as novel loci for adalimumab response in patients with Crohn's disease.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33750834","citation_count":15,"is_preprint":false},{"pmid":"30831207","id":"PMC_30831207","title":"Molecular cloning, phylogenetic analysis and functional characterisation of an Elovl7-like elongase from a marine crustacean, the orange mud crab (Scylla olivacea).","date":"2019","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30831207","citation_count":14,"is_preprint":false},{"pmid":"31242694","id":"PMC_31242694","title":"Fatty Acid Elongase 7 (ELOVL7) Plays a Role in the Synthesis of Long-Chain Unsaturated Fatty Acids in Goat Mammary Epithelial Cells.","date":"2019","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/31242694","citation_count":13,"is_preprint":false},{"pmid":"36291290","id":"PMC_36291290","title":"Glioblastoma Multiforme Tumors in Women Have a Lower Expression of Fatty Acid Elongases ELOVL2, ELOVL5, ELOVL6, and ELOVL7 than in Men.","date":"2022","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36291290","citation_count":9,"is_preprint":false},{"pmid":"37251958","id":"PMC_37251958","title":"Increased expression of ELOVL7 contributes to production of inflammatory cytokines in THP-1 cell-derived M1-like macrophages.","date":"2023","source":"Journal of clinical biochemistry and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/37251958","citation_count":6,"is_preprint":false},{"pmid":"33600908","id":"PMC_33600908","title":"Investigating ELOVL7 coding variants in multiple system atrophy.","date":"2021","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/33600908","citation_count":2,"is_preprint":false},{"pmid":"36930494","id":"PMC_36930494","title":"ELOVL fatty acid elongase 7 (ELOVL7), upregulated by Mdr2-knockout, predicts advanced liver fibrosis in patients with chronic hepatitis B.","date":"2023","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36930494","citation_count":2,"is_preprint":false},{"pmid":"41285716","id":"PMC_41285716","title":"Elovl7 sensitizes podocytes to ferroptosis in podocytopathy by elongating polyunsaturated fatty acids.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41285716","citation_count":0,"is_preprint":false},{"pmid":"40940503","id":"PMC_40940503","title":"Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids.","date":"2025","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/40940503","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.04.647255","title":"Lipid metabolism of hepatocyte-like cells supports intestinal tumor growth in  <i>Drosophila</i>","date":"2025-04-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.04.647255","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8331,"output_tokens":2088,"usd":0.028157,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9136,"output_tokens":2303,"usd":0.051627,"stage2_stop_reason":"end_turn"},"total_usd":0.079784,"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\": 2009,\n      \"finding\": \"ELOVL7 encodes a long-chain fatty acid elongase that preferentially elongates saturated very-long-chain fatty acids (SVLCFAs, C20:0 and longer), as demonstrated by in vitro fatty acid elongation assay and fatty acid composition analysis in prostate cancer cells.\",\n      \"method\": \"In vitro fatty acid elongation assay; fatty acid composition analysis (lipidomics); siRNA knockdown with lipid profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay combined with fatty acid composition analysis and knockdown, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19826053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ELOVL7 expression is transcriptionally regulated by the androgen pathway through the transcription factor SREBP1, similarly to other lipogenic enzymes in prostate cancer cells.\",\n      \"method\": \"Genome-wide gene expression analysis; pathway analysis linking androgen signaling to SREBP1-mediated ELOVL7 transcription in clinical prostate cancer samples\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — expression analysis with pathway linkage in clinical samples, single lab, mechanistic detail limited in abstract\",\n      \"pmids\": [\"19826053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Knockdown of ELOVL7 in prostate cancer cells reduced saturated very-long-chain fatty acids (SVLCFAs) in phospholipids and neutral lipids (including cholesterol ester), and attenuated de novo androgen synthesis, demonstrating a functional link between ELOVL7-mediated SVLCFA elongation and steroidogenesis.\",\n      \"method\": \"siRNA knockdown; lipid profiling of phospholipids and neutral lipids; de novo androgen synthesis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined lipid and steroidogenesis phenotype, single lab, multiple complementary readouts\",\n      \"pmids\": [\"19826053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In goat mammary epithelial cells, ELOVL7 overexpression increased the elongation index of C16:1 (palmitoleic acid) and altered concentrations of vaccenic acid (C18:1n7) and linoleic acid (C18:2), while overexpression decreased palmitoleic and oleic acid concentrations, indicating ELOVL7 preferentially elongates unsaturated C16–C18 fatty acids in this cell type.\",\n      \"method\": \"Overexpression and knockdown of ELOVL7 in goat mammary epithelial cells (GMEC); fatty acid composition analysis; elongation index calculation\",\n      \"journal\": \"Animals : an open access journal from MDPI\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with fatty acid profiling, single lab, two orthogonal perturbations\",\n      \"pmids\": [\"31242694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELOVL7 is upregulated in THP-1-derived M1-like macrophages via an NF-κB-dependent (not STAT1-dependent) transcriptional mechanism, and ELOVL7 knockdown decreases IL-6 and IL-12/IL-23 p40 production, placing ELOVL7 downstream of NF-κB signaling in the pro-inflammatory macrophage response.\",\n      \"method\": \"RNA-seq; NF-κB inhibitor (BAY11-7082) and STAT1 inhibitor (fludarabine) treatment; siRNA knockdown; cytokine ELISA; Metascape/GO enrichment analysis\",\n      \"journal\": \"Journal of clinical biochemistry and nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor epistasis plus KD with cytokine readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37251958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELOVL7 is upregulated in plasmacytoid dendritic cells (pDCs) treated with TLR7 and TLR9 agonists, suggesting ELOVL7 expression is induced downstream of innate immune receptor signaling in pDCs.\",\n      \"method\": \"RNA-seq of pDCs stimulated with TLR7/TLR9 agonists\",\n      \"journal\": \"Journal of clinical biochemistry and nutrition\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RNA-seq observation in pDCs, no functional follow-up reported in abstract\",\n      \"pmids\": [\"37251958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Upregulation of Elovl7 in injured podocytes leads to accumulation of phospholipids with long-chain polyunsaturated fatty acyl (LC-PUFA) tails, increasing lipid peroxidation and sensitizing podocytes to ferroptosis; this was confirmed by podocyte-specific Elovl7 knockout mice and Elovl7 knockdown podocyte cell lines.\",\n      \"method\": \"snRNA-seq; targeted lipidomics; podocyte-specific Elovl7 knockout mouse model; siRNA knockdown in podocyte cell line; ferroptosis scoring\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO plus in vitro KD, lipidomics, and functional ferroptosis readout; multiple orthogonal methods across cell and animal models\",\n      \"pmids\": [\"41285716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cardiac hypertrophy, fumarate hydratase (FH) suppresses ELOVL7 transcription via the SREBP transcription factor (malate-SREBP-Elovl7 axis); overexpression of Elovl7 reverses the cardioprotective effects of FH overexpression, establishing Elovl7 as a downstream effector of SREBP in pathological cardiac lipid remodeling.\",\n      \"method\": \"AAV9-mediated cardiomyocyte-specific FH overexpression; TAC mouse model; RNA sequencing; untargeted metabolomics; Elovl7 overexpression rescue experiment; SREBP knockdown\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (SREBP KD → Elovl7 reduction; Elovl7 OE reverses FH protection) with transcriptomics and metabolomics, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"40940503\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELOVL7 is a very-long-chain fatty acid elongase whose transcription is driven by SREBP (downstream of androgen signaling in prostate cancer and upstream of cardiac remodeling), and whose enzymatic activity elongates saturated VLCFAs (C20+) in prostate cells and unsaturated C16–C18 fatty acids in other contexts; accumulation of LC-PUFA-containing phospholipids via ELOVL7 sensitizes podocytes to ferroptosis, while in macrophages NF-κB-dependent ELOVL7 upregulation promotes IL-6 and IL-12/p40 production, collectively placing ELOVL7 at the intersection of lipid metabolism, inflammatory signaling, and cell death regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELOVL7 is a very-long-chain fatty acid elongase that sits at the intersection of lipid metabolism, SREBP-driven transcriptional programs, and inflammatory and cell-death signaling [#0, #6, #7]. Its core biochemical activity is the elongation of fatty acids: in prostate cancer cells it preferentially elongates saturated very-long-chain fatty acids (C20:0 and longer), and its knockdown reduces these species in both phospholipids and neutral lipids while attenuating de novo androgen synthesis, linking ELOVL7 elongation to steroidogenesis [#0, #2]. Substrate preference is context-dependent: in goat mammary epithelial cells ELOVL7 instead acts on unsaturated C16–C18 fatty acids [#3]. Transcriptionally, ELOVL7 is a downstream effector of SREBP — induced by androgen signaling via SREBP1 in prostate cancer [#1], and repressed through a malate–SREBP axis by fumarate hydratase in cardiac hypertrophy, where forced ELOVL7 expression reverses the cardioprotective effect of FH [#7]. In injured podocytes, ELOVL7 upregulation drives accumulation of phospholipids bearing long-chain polyunsaturated acyl tails, raising lipid peroxidation and sensitizing cells to ferroptosis, as confirmed by podocyte-specific knockout mice [#6]. In macrophages, NF-κB-dependent ELOVL7 induction promotes IL-6 and IL-12/IL-23 p40 production, placing the enzyme within the pro-inflammatory response [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the fundamental biochemical identity of ELOVL7 as an elongase with a defined substrate preference, and connected its lipid output to a physiological process (steroidogenesis) in prostate cancer.\",\n      \"evidence\": \"In vitro fatty acid elongation assay, lipidomic fatty acid composition analysis, and siRNA knockdown with androgen synthesis readout in prostate cancer cells\",\n      \"pmids\": [\"19826053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the elongase or catalytic mechanism\",\n        \"Substrate-selectivity determinants for C20+ saturated VLCFAs not defined\",\n        \"SREBP1 regulation inferred from expression/pathway analysis rather than direct promoter occupancy\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that ELOVL7 substrate preference is tissue-dependent, elongating unsaturated C16–C18 species in mammary epithelium rather than the saturated VLCFAs seen in prostate cells.\",\n      \"evidence\": \"Overexpression and knockdown in goat mammary epithelial cells with fatty acid profiling and elongation index calculation\",\n      \"pmids\": [\"31242694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism dictating saturated vs unsaturated substrate selection unknown\",\n        \"Cross-species relevance to human ELOVL7 not established\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed ELOVL7 within innate immune and inflammatory signaling by defining the transcriptional input (NF-κB, not STAT1) and a functional cytokine output in macrophages.\",\n      \"evidence\": \"RNA-seq, NF-κB/STAT1 pharmacological inhibitor epistasis, siRNA knockdown, and cytokine ELISA in THP-1-derived macrophages; RNA-seq of TLR7/9-stimulated pDCs\",\n      \"pmids\": [\"37251958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which lipid product mediates the cytokine effect is unresolved\",\n        \"pDC induction is a single RNA-seq observation without functional follow-up\",\n        \"Direct NF-κB binding to the ELOVL7 locus not shown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked ELOVL7 elongase activity to a specific cell-death mechanism, showing its LC-PUFA-phospholipid output sensitizes podocytes to ferroptosis in vivo.\",\n      \"evidence\": \"snRNA-seq, targeted lipidomics, podocyte-specific Elovl7 knockout mice, knockdown cell lines, and ferroptosis scoring\",\n      \"pmids\": [\"41285716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the same ferroptosis-sensitizing role operates in non-podocyte tissues is untested\",\n        \"Coupling between ELOVL7 product and peroxidation machinery not mechanistically dissected\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined ELOVL7 as a downstream effector node of a metabolite-controlled SREBP axis in pathological cardiac remodeling, with causal rescue establishing directionality.\",\n      \"evidence\": \"Cardiomyocyte-specific FH overexpression (AAV9), TAC model, RNA-seq, metabolomics, SREBP knockdown, and Elovl7 overexpression rescue in mice\",\n      \"pmids\": [\"40940503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which ELOVL7 lipid products drive cardiac hypertrophy not identified\",\n        \"Mechanism by which malate/FH modulates SREBP activity toward ELOVL7 not fully resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single elongase's product spectrum is redirected across tissues (saturated VLCFA vs LC-PUFA vs unsaturated C16–C18) to produce divergent outcomes — steroidogenesis, ferroptosis, inflammation, cardiac remodeling — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unifying model linking substrate selection to downstream phenotype\",\n        \"No structural or regulatory basis for context-dependent specificity\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}