{"gene":"ELOVL7","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2009,"finding":"ELOVL7 encodes a fatty acid elongase preferentially involved in elongation of saturated very-long-chain fatty acids (SVLCFAs, C20:0 and beyond), 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; ELOVL7 knockdown with lipid profile readout","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 — in vitro elongation assay with functional knockdown and lipid profiling, foundational paper with 163 citations","pmids":["19826053"],"is_preprint":false},{"year":2009,"finding":"ELOVL7 expression in prostate cancer is regulated by the androgen pathway through the transcription factor SREBP1, linking androgen signaling to saturated VLCFA metabolism.","method":"Gene expression analysis; androgen pathway perturbation; SREBP1 regulation of ELOVL7 in prostate cancer cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement by expression analysis with mechanistic follow-up, single lab","pmids":["19826053"],"is_preprint":false},{"year":2009,"finding":"ELOVL7 knockdown in prostate cancer cells affects SVLCFA content in phospholipids and cholesterol esters, and reduces de novo androgen synthesis, placing ELOVL7 in the steroidogenic pathway.","method":"siRNA knockdown; lipid profile analysis; de novo androgen synthesis measurement","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal biochemical readouts, 163 citations","pmids":["19826053"],"is_preprint":false},{"year":2019,"finding":"In goat mammary epithelial cells, ELOVL7 preferentially elongates unsaturated fatty acids (C16:1 and C18 series), as overexpression increases the elongation index of C16:1 and alters concentrations of vaccenic acid (C18:1n7) and linoleic acid (C18:2), while C16:0 and C18:0 are not preferred substrates.","method":"Overexpression and knockdown in primary goat mammary epithelial cells; fatty acid composition analysis; elongation index calculation","journal":"Animals","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation (OE and KD) with fatty acid profiling, single lab","pmids":["31242694"],"is_preprint":false},{"year":2023,"finding":"ELOVL7 expression in THP-1 cell-derived M1-like macrophages is upregulated by NF-κB signaling (not STAT1), and ELOVL7 knockdown reduces IL-6 and IL-12/IL-23 p40 cytokine production, placing ELOVL7 downstream of NF-κB in macrophage inflammatory responses.","method":"NF-κB inhibitor (BAY11-7082) treatment; siRNA knockdown; cytokine ELISA; RNA-seq; pharmacological inhibition of STAT1","journal":"Journal of clinical biochemistry and nutrition","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via inhibitors combined with KD and cytokine readout, single lab","pmids":["37251958"],"is_preprint":false},{"year":2025,"finding":"Fumarate hydratase (FH) overexpression in cardiomyocytes suppresses cardiac hypertrophy by reducing SREBP transcription factor activity, which in turn decreases Elovl7 gene expression; overexpression of Elovl7 reverses the cardioprotective effect of FH, placing Elovl7 downstream of the malate-SREBP axis in cardiac lipid metabolism.","method":"AAV9-mediated FH overexpression in TAC mice; RNA sequencing; untargeted metabolomics; Elovl7 overexpression rescue experiment; SREBP knockdown","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via rescue experiment with multiple orthogonal methods, single lab, no replication yet","pmids":["40940503"],"is_preprint":false},{"year":2025,"finding":"Upregulation of Elovl7 in injured podocytes drives accumulation of phospholipids with long-chain polyunsaturated fatty acid (LC-PUFA) tails, increasing lipid peroxidation and sensitizing podocytes to ferroptosis; podocyte-specific Elovl7 knockout mice and Elovl7 knockdown podocyte cell lines confirmed this mechanism.","method":"Single-nucleus RNA sequencing; targeted lipidomics; podocyte-specific knockout mice; siRNA knockdown; ferroptosis assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 — loss-of-function in vivo (KO mice) and in vitro (KD) with targeted lipidomics and defined ferroptosis phenotype","pmids":["41285716"],"is_preprint":false},{"year":2025,"finding":"In a mouse lung tumor model, tumors increase hepatic expression of Elovl7 (along with Hnf4), and reducing Elovl7 expression suppresses tumor growth, tracheogenesis, and cachexia-like phenotypes, suggesting Elovl7-mediated VLCFA production in hepatocytes supports distal tumor growth.","method":"Mouse lung tumor model; hepatic gene expression analysis; genetic reduction of elongase expression; lifespan and tumor growth readouts","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 — mechanistic claim in mammals is secondary finding in a Drosophila-focused study, single method in mammalian context, preprint","pmids":["bio_10.1101_2025.04.04.647255"],"is_preprint":true}],"current_model":"ELOVL7 is a fatty acid elongase that preferentially extends saturated and certain unsaturated very-long-chain fatty acids, regulated transcriptionally by SREBP1 (downstream of androgen signaling and fumarate/malate metabolic signals), and its activity feeds into phospholipid remodeling pathways that affect cholesterol ester-dependent de novo androgen synthesis, macrophage NF-κB-driven cytokine production, and podocyte ferroptosis sensitivity via LC-PUFA accumulation and lipid peroxidation."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing ELOVL7 as an SVLCFA elongase linked to androgen-dependent prostate cancer metabolism answered the question of what enzymatic activity the gene encodes and placed it in a disease-relevant lipid pathway.","evidence":"In vitro fatty acid elongation assay, siRNA knockdown with lipid profiling and de novo androgen synthesis measurement in prostate cancer cells","pmids":["19826053"],"confidence":"High","gaps":["Structural basis for substrate selectivity (saturated vs. unsaturated VLCFAs) not determined","Whether ELOVL7-dependent cholesterol ester remodeling is required for androgen synthesis in vivo remains untested","Transcriptional regulation by SREBP1 demonstrated in one cell system only"]},{"year":2019,"claim":"Demonstrating that ELOVL7 also elongates unsaturated fatty acids (C16:1, C18 series) in mammary epithelial cells broadened the substrate profile beyond saturated VLCFAs and indicated tissue-dependent substrate preference.","evidence":"Overexpression and knockdown in primary goat mammary epithelial cells with fatty acid composition analysis and elongation index calculation","pmids":["31242694"],"confidence":"Medium","gaps":["Species-specific substrate selectivity not resolved against human orthologue","No purified enzyme kinetics to quantify relative affinities for saturated vs. unsaturated substrates","Single lab, awaits independent replication"]},{"year":2023,"claim":"Identifying NF-κB as the transcriptional driver of ELOVL7 in M1-like macrophages, and showing that ELOVL7 knockdown suppresses IL-6 and IL-12/IL-23 p40 production, established a role for ELOVL7 in innate immune inflammatory output.","evidence":"NF-κB and STAT1 inhibitor epistasis, siRNA knockdown, and cytokine ELISA in THP-1-derived macrophages","pmids":["37251958"],"confidence":"Medium","gaps":["Which ELOVL7-generated lipid species mediate cytokine regulation is unknown","Not tested in primary human macrophages or in vivo inflammatory models","Single lab without independent confirmation"]},{"year":2025,"claim":"Positioning ELOVL7 downstream of the fumarate hydratase–malate–SREBP axis in cardiomyocytes, where its overexpression reverses FH-mediated cardioprotection, revealed a metabolic node linking TCA cycle intermediates to pathological cardiac lipid remodeling.","evidence":"AAV9-FH overexpression in TAC mice, RNA-seq, metabolomics, Elovl7 overexpression rescue, SREBP knockdown","pmids":["40940503"],"confidence":"Medium","gaps":["Specific VLCFA species mediating cardiac hypertrophy not identified","Single lab, no independent replication yet","Whether cardiac ELOVL7 regulation by SREBP shares the same promoter elements as in prostate cancer is unresolved"]},{"year":2025,"claim":"Showing that podocyte ELOVL7 upregulation drives LC-PUFA-containing phospholipid accumulation, lipid peroxidation, and ferroptosis — validated by podocyte-specific knockout — established ELOVL7 as a determinant of ferroptosis susceptibility through membrane lipid composition.","evidence":"Single-nucleus RNA-seq, targeted lipidomics, podocyte-specific Elovl7 knockout mice, siRNA knockdown, ferroptosis assays","pmids":["41285716"],"confidence":"High","gaps":["Direct identification of the peroxidation-prone phospholipid species generated by ELOVL7 is incomplete","Whether ELOVL7-driven ferroptosis sensitization operates in cell types beyond podocytes is untested","Interaction with GPX4 or other ferroptosis defense systems not characterized"]},{"year":null,"claim":"No crystal or cryo-EM structure of ELOVL7 exists, the molecular basis for its dual saturated/unsaturated substrate selectivity is unresolved, and in vivo contributions of ELOVL7 to systemic lipid homeostasis in full-body knockout models have not been reported.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of ELOVL7","No full-body knockout phenotyping reported","Relative contributions of ELOVL7 vs. other ELOVL family members to overlapping substrates not dissected in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":[],"partners":["SREBF1"],"other_free_text":[]},"mechanistic_narrative":"ELOVL7 is a fatty acid elongase that extends saturated and unsaturated very-long-chain fatty acids, functioning in phospholipid and cholesterol ester remodeling with downstream consequences for steroidogenesis, inflammation, and cell death. ELOVL7 preferentially elongates saturated VLCFAs (≥C20:0) in prostate cancer cells, where its knockdown depletes SVLCFA-containing lipid species and reduces de novo androgen synthesis, and also elongates unsaturated fatty acids (C16:1, C18 series) in mammary epithelial cells [PMID:19826053, PMID:31242694]. Transcriptionally, ELOVL7 is regulated by SREBP1 downstream of androgen signaling and the fumarate hydratase–malate metabolic axis, and by NF-κB in M1-polarized macrophages, where it promotes IL-6 and IL-12/IL-23 p40 cytokine secretion [PMID:19826053, PMID:40940503, PMID:37251958]. In injured podocytes, ELOVL7 upregulation drives accumulation of phospholipids bearing long-chain polyunsaturated fatty acid tails, increasing lipid peroxidation and sensitizing cells to ferroptosis, as confirmed by podocyte-specific knockout in mice [PMID:41285716]."},"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":163,"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":31,"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":14,"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":12,"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":"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":"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":"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":"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":null,"id":"bio_10.1101_2025.04.04.647255","title":"Lipid metabolism of hepatocyte-like cells supports intestinal tumor growth by promoting tracheogenesis","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":7634,"output_tokens":1881,"usd":0.025559},"stage2":{"model":"claude-opus-4-6","input_tokens":5167,"output_tokens":1904,"usd":0.110153},"total_usd":0.135712,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"ELOVL7 encodes a fatty acid elongase preferentially involved in elongation of saturated very-long-chain fatty acids (SVLCFAs, C20:0 and beyond), 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; ELOVL7 knockdown with lipid profile readout\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro elongation assay with functional knockdown and lipid profiling, foundational paper with 163 citations\",\n      \"pmids\": [\"19826053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ELOVL7 expression in prostate cancer is regulated by the androgen pathway through the transcription factor SREBP1, linking androgen signaling to saturated VLCFA metabolism.\",\n      \"method\": \"Gene expression analysis; androgen pathway perturbation; SREBP1 regulation of ELOVL7 in prostate cancer cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement by expression analysis with mechanistic follow-up, single lab\",\n      \"pmids\": [\"19826053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ELOVL7 knockdown in prostate cancer cells affects SVLCFA content in phospholipids and cholesterol esters, and reduces de novo androgen synthesis, placing ELOVL7 in the steroidogenic pathway.\",\n      \"method\": \"siRNA knockdown; lipid profile analysis; de novo androgen synthesis measurement\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal biochemical readouts, 163 citations\",\n      \"pmids\": [\"19826053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In goat mammary epithelial cells, ELOVL7 preferentially elongates unsaturated fatty acids (C16:1 and C18 series), as overexpression increases the elongation index of C16:1 and alters concentrations of vaccenic acid (C18:1n7) and linoleic acid (C18:2), while C16:0 and C18:0 are not preferred substrates.\",\n      \"method\": \"Overexpression and knockdown in primary goat mammary epithelial cells; fatty acid composition analysis; elongation index calculation\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (OE and KD) with fatty acid profiling, single lab\",\n      \"pmids\": [\"31242694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELOVL7 expression in THP-1 cell-derived M1-like macrophages is upregulated by NF-κB signaling (not STAT1), and ELOVL7 knockdown reduces IL-6 and IL-12/IL-23 p40 cytokine production, placing ELOVL7 downstream of NF-κB in macrophage inflammatory responses.\",\n      \"method\": \"NF-κB inhibitor (BAY11-7082) treatment; siRNA knockdown; cytokine ELISA; RNA-seq; pharmacological inhibition of STAT1\",\n      \"journal\": \"Journal of clinical biochemistry and nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via inhibitors combined with KD and cytokine readout, single lab\",\n      \"pmids\": [\"37251958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fumarate hydratase (FH) overexpression in cardiomyocytes suppresses cardiac hypertrophy by reducing SREBP transcription factor activity, which in turn decreases Elovl7 gene expression; overexpression of Elovl7 reverses the cardioprotective effect of FH, placing Elovl7 downstream of the malate-SREBP axis in cardiac lipid metabolism.\",\n      \"method\": \"AAV9-mediated FH overexpression in TAC mice; RNA sequencing; untargeted metabolomics; Elovl7 overexpression rescue experiment; SREBP knockdown\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via rescue experiment with multiple orthogonal methods, single lab, no replication yet\",\n      \"pmids\": [\"40940503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Upregulation of Elovl7 in injured podocytes drives accumulation of phospholipids with long-chain polyunsaturated fatty acid (LC-PUFA) tails, increasing lipid peroxidation and sensitizing podocytes to ferroptosis; podocyte-specific Elovl7 knockout mice and Elovl7 knockdown podocyte cell lines confirmed this mechanism.\",\n      \"method\": \"Single-nucleus RNA sequencing; targeted lipidomics; podocyte-specific knockout mice; siRNA knockdown; ferroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — loss-of-function in vivo (KO mice) and in vitro (KD) with targeted lipidomics and defined ferroptosis phenotype\",\n      \"pmids\": [\"41285716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a mouse lung tumor model, tumors increase hepatic expression of Elovl7 (along with Hnf4), and reducing Elovl7 expression suppresses tumor growth, tracheogenesis, and cachexia-like phenotypes, suggesting Elovl7-mediated VLCFA production in hepatocytes supports distal tumor growth.\",\n      \"method\": \"Mouse lung tumor model; hepatic gene expression analysis; genetic reduction of elongase expression; lifespan and tumor growth readouts\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic claim in mammals is secondary finding in a Drosophila-focused study, single method in mammalian context, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.04.04.647255\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ELOVL7 is a fatty acid elongase that preferentially extends saturated and certain unsaturated very-long-chain fatty acids, regulated transcriptionally by SREBP1 (downstream of androgen signaling and fumarate/malate metabolic signals), and its activity feeds into phospholipid remodeling pathways that affect cholesterol ester-dependent de novo androgen synthesis, macrophage NF-κB-driven cytokine production, and podocyte ferroptosis sensitivity via LC-PUFA accumulation and lipid peroxidation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ELOVL7 is a fatty acid elongase that extends saturated and unsaturated very-long-chain fatty acids, functioning in phospholipid and cholesterol ester remodeling with downstream consequences for steroidogenesis, inflammation, and cell death. ELOVL7 preferentially elongates saturated VLCFAs (≥C20:0) in prostate cancer cells, where its knockdown depletes SVLCFA-containing lipid species and reduces de novo androgen synthesis, and also elongates unsaturated fatty acids (C16:1, C18 series) in mammary epithelial cells [PMID:19826053, PMID:31242694]. Transcriptionally, ELOVL7 is regulated by SREBP1 downstream of androgen signaling and the fumarate hydratase–malate metabolic axis, and by NF-κB in M1-polarized macrophages, where it promotes IL-6 and IL-12/IL-23 p40 cytokine secretion [PMID:19826053, PMID:40940503, PMID:37251958]. In injured podocytes, ELOVL7 upregulation drives accumulation of phospholipids bearing long-chain polyunsaturated fatty acid tails, increasing lipid peroxidation and sensitizing cells to ferroptosis, as confirmed by podocyte-specific knockout in mice [PMID:41285716].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing ELOVL7 as an SVLCFA elongase linked to androgen-dependent prostate cancer metabolism answered the question of what enzymatic activity the gene encodes and placed it in a disease-relevant lipid pathway.\",\n      \"evidence\": \"In vitro fatty acid elongation assay, siRNA knockdown with lipid profiling and de novo androgen synthesis measurement in prostate cancer cells\",\n      \"pmids\": [\"19826053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for substrate selectivity (saturated vs. unsaturated VLCFAs) not determined\",\n        \"Whether ELOVL7-dependent cholesterol ester remodeling is required for androgen synthesis in vivo remains untested\",\n        \"Transcriptional regulation by SREBP1 demonstrated in one cell system only\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that ELOVL7 also elongates unsaturated fatty acids (C16:1, C18 series) in mammary epithelial cells broadened the substrate profile beyond saturated VLCFAs and indicated tissue-dependent substrate preference.\",\n      \"evidence\": \"Overexpression and knockdown in primary goat mammary epithelial cells with fatty acid composition analysis and elongation index calculation\",\n      \"pmids\": [\"31242694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Species-specific substrate selectivity not resolved against human orthologue\",\n        \"No purified enzyme kinetics to quantify relative affinities for saturated vs. unsaturated substrates\",\n        \"Single lab, awaits independent replication\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying NF-κB as the transcriptional driver of ELOVL7 in M1-like macrophages, and showing that ELOVL7 knockdown suppresses IL-6 and IL-12/IL-23 p40 production, established a role for ELOVL7 in innate immune inflammatory output.\",\n      \"evidence\": \"NF-κB and STAT1 inhibitor epistasis, siRNA knockdown, and cytokine ELISA in THP-1-derived macrophages\",\n      \"pmids\": [\"37251958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which ELOVL7-generated lipid species mediate cytokine regulation is unknown\",\n        \"Not tested in primary human macrophages or in vivo inflammatory models\",\n        \"Single lab without independent confirmation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioning ELOVL7 downstream of the fumarate hydratase–malate–SREBP axis in cardiomyocytes, where its overexpression reverses FH-mediated cardioprotection, revealed a metabolic node linking TCA cycle intermediates to pathological cardiac lipid remodeling.\",\n      \"evidence\": \"AAV9-FH overexpression in TAC mice, RNA-seq, metabolomics, Elovl7 overexpression rescue, SREBP knockdown\",\n      \"pmids\": [\"40940503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific VLCFA species mediating cardiac hypertrophy not identified\",\n        \"Single lab, no independent replication yet\",\n        \"Whether cardiac ELOVL7 regulation by SREBP shares the same promoter elements as in prostate cancer is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that podocyte ELOVL7 upregulation drives LC-PUFA-containing phospholipid accumulation, lipid peroxidation, and ferroptosis — validated by podocyte-specific knockout — established ELOVL7 as a determinant of ferroptosis susceptibility through membrane lipid composition.\",\n      \"evidence\": \"Single-nucleus RNA-seq, targeted lipidomics, podocyte-specific Elovl7 knockout mice, siRNA knockdown, ferroptosis assays\",\n      \"pmids\": [\"41285716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct identification of the peroxidation-prone phospholipid species generated by ELOVL7 is incomplete\",\n        \"Whether ELOVL7-driven ferroptosis sensitization operates in cell types beyond podocytes is untested\",\n        \"Interaction with GPX4 or other ferroptosis defense systems not characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No crystal or cryo-EM structure of ELOVL7 exists, the molecular basis for its dual saturated/unsaturated substrate selectivity is unresolved, and in vivo contributions of ELOVL7 to systemic lipid homeostasis in full-body knockout models have not been reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of ELOVL7\",\n        \"No full-body knockout phenotyping reported\",\n        \"Relative contributions of ELOVL7 vs. other ELOVL family members to overlapping substrates not dissected in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0016740\",\n        \"supporting_discovery_ids\": [0, 3]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005783\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1430728\",\n        \"supporting_discovery_ids\": [0, 2, 3, 6]\n      },\n      {\n        \"term_id\": \"R-HSA-5357801\",\n        \"supporting_discovery_ids\": [6]\n      },\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [4]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SREBF1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}