{"gene":"ELOVL6","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2007,"finding":"ELOVL6 is the elongase that catalyzes the conversion of palmitate (C16:0) to stearate (C18:0); deletion of Elovl6 in mice causes accumulation of C16 fatty acids and loss of C18 species. Loss of Elovl6 protects against obesity-induced insulin resistance by restoring hepatic insulin receptor substrate-2 (IRS-2) and suppressing hepatic protein kinase C epsilon (PKCε) activity, thereby restoring Akt phosphorylation.","method":"Elovl6 knockout mouse model; high-fat diet and ob/ob cross; measurement of hepatic fatty acid composition, IRS-2, PKCε activity, and Akt phosphorylation","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with multiple orthogonal biochemical readouts; foundational paper replicated widely","pmids":["17906635"],"is_preprint":false},{"year":2008,"finding":"The mouse Elovl6 gene promoter is a direct transcriptional target of SREBP-1c; two sterol regulatory elements (SRE-1 and SRE-2) in the promoter bind SREBP, with SRE-1 having higher affinity; adenoviral RNAi knockdown of SREBP-1 in mouse liver suppresses Elovl6 mRNA.","method":"Luciferase reporter assay; EMSA; chromatin immunoprecipitation (ChIP); adenoviral RNAi in mouse liver","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (reporter assay, EMSA, ChIP, in vivo RNAi) in single study","pmids":["18226595"],"is_preprint":false},{"year":2011,"finding":"ELOVL6 is a microsomal enzyme elongating C12–C16 saturated and monounsaturated fatty acids; in pancreatic β-cells, Elovl6 knockdown limits palmitate elongation to stearate and increases palmitoleate production, attenuating palmitate-induced ER stress and apoptosis; conversely, Elovl6 overexpression increases palmitate elongation to stearate and enhances ER stress and apoptosis.","method":"siRNA knockdown and overexpression in INS-1 β-cells; fatty acid radiolabeling to track elongation; measurement of ER stress markers and apoptosis","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function with biochemical substrate tracking and multiple cellular readouts","pmids":["21266672"],"is_preprint":false},{"year":2011,"finding":"Macrophage-specific Elovl6 deficiency reduces foam cell formation by increasing cholesterol efflux and expression of cholesterol efflux transporters; absence of Elovl6 decreases n-6 polyunsaturated fatty acids in the esterified cholesterol fraction of macrophages; bone marrow transplantation of Elovl6-/- cells into LDL-R-/- mice reduces atherosclerotic lesion area.","method":"Bone marrow transplantation into LDL-R-/- mice; peritoneal macrophage isolation; acetylated-LDL uptake and cholesterol efflux assays; fatty acid composition analysis","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo bone marrow transplant plus multiple ex vivo mechanistic assays","pmids":["21817094"],"is_preprint":false},{"year":2012,"finding":"Elovl6 promotes nonalcoholic steatohepatitis (NASH); deletion of Elovl6 reduces palmitate-induced activation of the NLRP3 inflammasome, which is a mechanistic basis for Elovl6-mediated modulation of hepatic inflammation, oxidative stress, and fibrosis.","method":"Elovl6 loss- and gain-of-function mouse models; NLRP3 inflammasome activation assays; human NASH liver samples for correlation","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — three independent mouse models plus in vitro inflammasome assays","pmids":["22753171"],"is_preprint":false},{"year":2013,"finding":"Elovl6 is a rate-limiting enzyme for elongation of saturated and monounsaturated fatty acids; its deficiency in mice causes derangement of fatty acid profile and leads to severe fibroproliferative response after bleomycin-induced lung injury; Elovl6 knockdown induces apoptosis, TGF-β1 expression, and reactive oxygen species generation in alveolar type II epithelial cells.","method":"Elovl6-/- mouse model with intratracheal bleomycin; siRNA knockdown in lung epithelial cells; measurement of apoptosis, TGF-β1, and ROS","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — KO mouse phenotype plus in vitro knockdown with multiple mechanistic readouts","pmids":["24113622"],"is_preprint":false},{"year":2014,"finding":"ELOVL6 is the only enzyme capable of elongating palmitate (C16:0) to stearate (C18:0) in vivo; Elovl6-/- mouse livers accumulate C16:0 and C16:1 n-7 with loss of C18:0 and C18:1 n-9, confirming substrate specificity. Palmitoleate (C16:1 n-7) to vaccenate (C18:1 n-7) elongation was not specific to ELOVL6.","method":"Elovl6 knockout mouse generation; hepatic fatty acid composition analysis by mass spectrometry; dietary intervention studies","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — definitive substrate specificity established by KO + detailed lipidomics in vivo","pmids":["25281760"],"is_preprint":false},{"year":2014,"finding":"ELOVL6 activity regulates fatty acid composition in pancreatic islets; in Elovl6-/- mice fed a high-fat/high-sucrose diet, improved glucose-stimulated insulin secretion (GSIS) is associated with increased islet ATP/ADP ratio and suppression of ATF-3 expression.","method":"Elovl6-/- mouse model; high-fat/high-sucrose diet; isolated islet glucose-stimulated insulin secretion assay; ATP/ADP ratio measurement; ATF-3 expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype, but single lab single study","pmids":["24938128"],"is_preprint":false},{"year":2014,"finding":"ELOVL6 enzymatic activity is regulated by the 3-ketoacyl-CoA reductase KAR via two modes: (1) KAR induces conformational changes in ELOVL6 independent of KAR enzyme activity, enhancing ELOVL6 activity ~3-fold; (2) KAR enzyme activity-dependent conversion of 3-ketoacyl-CoA to 3-hydroxyacyl-CoA facilitates product release from a presumed ELOVL6-KAR complex, further enhancing activity ~10-fold in the presence of NADPH.","method":"In vitro fatty acid elongation assay using membrane fractions; purified ELOVL6; KAR mutants; NADPH-dependence experiments","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with purified proteins and mutagenesis","pmids":["25003994"],"is_preprint":false},{"year":2015,"finding":"Elovl6 is necessary for thermogenic function of brown adipose tissue (BAT); loss of Elovl6 causes reduced expression of mitochondrial electron transport chain components and lower BAT thermogenic capacity without altering classical BAT markers; this is compensated by increased beiging of subcutaneous white adipose tissue.","method":"Elovl6 KO mice; cold exposure experiments; mitochondrial ETC component expression; BAT oxygen consumption; thermoneutrality and aging studies","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple physiological and molecular readouts across multiple conditions","pmids":["26628376"],"is_preprint":false},{"year":2016,"finding":"Elovl6 inhibition in vascular smooth muscle cells (VSMCs) causes increased palmitate and reduced oleate levels, leading to ROS production, AMPK activation, induction of KLF4 (a pluripotency gene), and phenotypic switching of VSMCs including growth arrest and downregulation of VSMC markers; KLF4 knockdown attenuates AMPK-induced phenotypic switching, establishing KLF4 as a bona fide AMPK target in this pathway.","method":"Elovl6-/- mouse neointima wire-injury model; siRNA knockdown in cultured VSMCs; PDGF-BB stimulation; ROS measurement; AMPK and mTOR phosphorylation; KLF4 knockdown epistasis","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO phenotype plus in vitro mechanistic pathway dissection with epistasis experiment","pmids":["27881420"],"is_preprint":false},{"year":2016,"finding":"Elovl6 plays a critical role in chondrocyte growth and differentiation during growth plate development; Elovl6-/- mice show reduced chondrocyte proliferation and accelerated hypertrophic differentiation, associated with increased Collagen10α1 expression and elevated Foxa2/a3 and Mef2c mRNA; increased nuclear Foxa2 and cytoplasmic HDAC4/5/7 protein levels are observed in Elovl6 knockdown chondrocytes.","method":"Elovl6 KO mouse skeletal analysis; histology; gene expression; siRNA knockdown in chondrocyte cell lines; protein localization by fractionation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse phenotype plus in vitro mechanistic follow-up, single lab","pmids":["27467521"],"is_preprint":false},{"year":2017,"finding":"Elovl6 deletion in db/db mice markedly increases β-cell mass with increased proliferation and decreased apoptosis; Elovl6 deletion suppresses oleate (C18:1n-9) elevation in islets, cell stress, and inflammation; isolated Elovl6-/- islets show reduced susceptibility to palmitate-induced ER stress, inflammation, and β-cell apoptosis; oleate-treated islets impair glucose-stimulated insulin secretion regardless of Elovl6 genotype, implicating oleate as a key lipotoxic mediator.","method":"Elovl6 deletion in db/db mouse model; β-cell mass morphometry; islet isolation; ex vivo palmitate and oleate treatment; ER stress markers; GSIS assay","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model plus multiple ex vivo mechanistic experiments with clear pathway placement","pmids":["28461456"],"is_preprint":false},{"year":2018,"finding":"Elovl6 in keratinocytes regulates fatty acid composition; Elovl6-/- mice have higher levels of cis-vaccenic acid (CVA) in the epidermis; CVA accelerates tape stripping-triggered keratinocyte death and release of DAMPs (HMGB-1 and IL-1α), which induce proinflammatory cytokine and chemokine production (IL-1β, CXCL-1).","method":"Elovl6-/- mouse tape-stripping model; epidermal fatty acid composition analysis; DAMP measurement; cytokine/chemokine quantification","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with mechanistic follow-up, single lab","pmids":["30518914"],"is_preprint":false},{"year":2018,"finding":"In a Drosophila model (Baldspot/ELOVL6 ortholog), loss of Baldspot rescues retinal degeneration in a model of ER stress (Rh1G69D) and reduces IRE1 and PERK signaling and cell death; dietary supplementation with stearate bypasses the need for Baldspot activity, linking the enzyme's conversion of C16 to C18 to ER stress modulation.","method":"Drosophila Baldspot knockout; Rh1G69D ER stress model; IRE1 and PERK signaling assays; dietary stearate supplementation rescue","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — ortholog genetic model with epistasis and dietary rescue, single lab","pmids":["30081392"],"is_preprint":false},{"year":2021,"finding":"ELOVL6 directly interacts with ACSL4 (a key regulator of ferroptosis), as confirmed by co-immunoprecipitation; ELOVL6 overexpression in colorectal cancer HCT116 cells reverses apatinib-induced ferroptosis, indicating ELOVL6 acts upstream of ACSL4-mediated ferroptotic signaling.","method":"Co-immunoprecipitation; ELOVL6 overexpression; CCK-8 cell viability; ROS and iron measurement; Western blot for ferroptosis markers","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus functional overexpression data, single lab","pmids":["33603479"],"is_preprint":false},{"year":2021,"finding":"ELOVL6 levels regulate bortezomib (BTZ) sensitivity in multiple myeloma cells; ELOVL6 depletion suppresses BTZ-induced ER stress and cytotoxicity; restoration of ELOVL6 in BTZ-resistant cells resensitizes them to BTZ via upregulation of ELOVL6-dependent ceramide species, which are required for BTZ-induced ER stress and cell death.","method":"ELOVL6 knockdown and overexpression in MM cell lines; BTZ treatment; lipidomic profiling; ceramide measurement; xenograft plasmacytoma mouse model","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (lipidomics, in vitro gain/loss of function, in vivo xenograft) in single study","pmids":["33821992"],"is_preprint":false},{"year":2022,"finding":"ELOVL6 deficiency in mice aggravates allergic airway inflammation; lipidomic profiling revealed elevated palmitic acid, ceramides, and sphingosine-1-phosphate (S1P) in Elovl6-/- mouse lungs after sensitization; treatment with inhibitors of ceramide synthase (fumonisin B1) or sphingosine kinase (DL-threo-dihydrosphingosine) ameliorated the aggravated inflammation, placing ELOVL6 upstream of the ceramide-S1P biosynthesis pathway in airway immune regulation.","method":"Elovl6-/- mouse ovalbumin and house dust mite asthma models; lipidomic profiling; pharmacological inhibition of ceramide synthase and sphingosine kinase; cellular immunology assays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with lipidomics and pharmacological epistasis establishing pathway mechanism","pmids":["36592705"],"is_preprint":false},{"year":2023,"finding":"ELOVL6 is upregulated in myelin-phagocytosing macrophages and in MS lesions; Elovl6 depletion induces a repair-promoting phagocyte phenotype through activation of the S1P/PPARγ pathway, enhances ABCA1-mediated lipid efflux, increases neurotrophic factor production, and reduces inflammatory mediator expression; Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the cuprizone mouse model.","method":"In vitro myelin phagocytosis model; Elovl6-/- macrophages; S1P/PPARγ pathway analysis; ABCA1-mediated cholesterol efflux assay; organotypic brain slice cultures; cuprizone mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vitro and in vivo models with defined molecular pathway","pmids":["37669365"],"is_preprint":false},{"year":2023,"finding":"miR-135b-5p, miR-135a-5p, miR-125a-5p, miR-125b-5p, and miR-22-3p directly bind the 3'-UTR of human ELOVL6 mRNA and downregulate its expression; miR-135b-5p and miR-135a-5p suppress glioblastoma cell proliferation and migration by inhibiting ELOVL6 at both mRNA and protein levels.","method":"Dual-luciferase reporter assay with ELOVL6 3'-UTR; miRNA overexpression in glioblastoma cells; cell proliferation and migration assays; qRT-PCR and Western blot","journal":"BBA advances","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter plus functional cellular assays, single lab","pmids":["37082255"],"is_preprint":false},{"year":2025,"finding":"c-MYC directly upregulates ELOVL6 expression during pancreatic cancer (PDAC) tumor progression; genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability, and pinocytosis; in vivo ELOVL6 inhibition suppresses tumor growth and improves Abraxane response.","method":"PDAC mouse models and cell lines; c-MYC overexpression/inhibition; ELOVL6 genetic knockdown and chemical inhibitor; fatty acid composition analysis; membrane property measurements; in vivo tumor growth and survival","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple in vitro and in vivo models with defined molecular mechanism and pathway placement","pmids":["39956817"],"is_preprint":false},{"year":2025,"finding":"ELOVL6 controls phospholipid production exploited by KRAS-G12V for membrane association; CRISPR-Cas9 genome-wide knockout screen identified ELOVL6 as a selective modulator of KRAS-G12V protein expression; ELOVL6 attenuation induces degradation of KRAS-G12V protein through altered phospholipid composition, reducing aberrant oncogenic signaling.","method":"CRISPR-Cas9 genome-wide KO screen; ELOVL6 inhibition in KRAS-G12V cancer cells; phospholipidomics; KRAS protein expression and degradation assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide functional screen plus lipidomics and protein degradation mechanism, single study","pmids":["40954224"],"is_preprint":false},{"year":2009,"finding":"A selective radioligand ([(3)H]Compound-A) was identified for ELOVL6 that binds in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH, suggesting Compound-A recognizes an enzyme-substrate (acyl-enzyme intermediate) complex; Compound-A inhibits human and mouse ELOVL6 with >100-fold selectivity over other ELOVL family members.","method":"Radioligand binding assay; enzyme inhibition assay; selectivity profiling against ELOVL family members; substrate-dependence studies","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — biochemical binding and inhibition assays with mechanistic inference about active site, single lab","pmids":["19505953"],"is_preprint":false},{"year":2025,"finding":"ELOVL6 knockdown in FGFR3-mutant bladder cancer cells markedly reduces phosphatidylethanolamine levels, impairs mitochondrial complex I and II protein expression and mitochondrial oxidative phosphorylation (OXPHOS), and activates the ECM-integrin-FAK pathway as a compensatory response; these data establish that ELOVL6 regulates lipid composition to preserve mitochondrial function.","method":"ELOVL6 siRNA knockdown in BC cell lines; lipidomics; mitochondrial OXPHOS measurement; RNA sequencing; in vivo tumor growth","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — lipidomics plus functional mitochondrial assays with transcriptomics, single lab","pmids":["40835210"],"is_preprint":false},{"year":2021,"finding":"SREBP1 directly binds to SRE1 and SRE3 elements in the goat ELOVL6 promoter to regulate its transcription; mutation of both SRE sites abolishes SREBP1-stimulated and linoleic acid-repressed ELOVL6 promoter activity; chromatin immunoprecipitation confirmed in vivo SREBP1 binding at these sites in goat mammary epithelial cells.","method":"Promoter deletion analysis; site-directed mutagenesis; luciferase reporter assay; chromatin immunoprecipitation in goat mammary epithelial cells","journal":"Journal of dairy science","confidence":"Medium","confidence_rationale":"Tier 1-2 — multiple orthogonal promoter analyses in a non-rodent mammalian system, single lab","pmids":["33685712"],"is_preprint":false}],"current_model":"ELOVL6 is a microsomal fatty acid elongase that catalyzes the rate-limiting condensation step converting C16 saturated and monounsaturated fatty acids (palmitate, palmitoleate) to their C18 counterparts (stearate, oleate), a reaction directly regulated at the transcriptional level by SREBP-1c binding to SRE elements in the promoter; its enzymatic activity is further modulated post-translationally by physical interaction with the downstream elongation cycle enzyme KAR, which enhances ELOVL6 activity both through conformational change and via product-release facilitation; by controlling the C16/C18 fatty acid balance, ELOVL6 shapes membrane lipid composition (including ceramide and phospholipid species) to regulate insulin signaling (via IRS-2 and PKCε/Akt), NLRP3 inflammasome activation, ER stress responses (via IRE1/PERK and ceramide), mitochondrial function, and VSMC phenotypic switching (via ROS/AMPK/KLF4), establishing cellular fatty acid composition as a broadly important determinant of metabolic and inflammatory homeostasis."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing the core enzymatic function of ELOVL6 and its metabolic significance: the foundational question of which elongase converts C16:0 to C18:0 was resolved, revealing that ELOVL6 loss protects against obesity-induced insulin resistance by modulating hepatic PKCε/IRS-2/Akt signaling.","evidence":"Elovl6 knockout mouse on high-fat diet and ob/ob background with hepatic fatty acid profiling and insulin signaling readouts","pmids":["17906635"],"confidence":"High","gaps":["Substrate specificity among other chain lengths and unsaturated species not fully delineated","Whether protection from insulin resistance is cell-autonomous in hepatocytes versus systemic","Mechanism linking altered C16/C18 ratio to PKCε activity not defined"]},{"year":2008,"claim":"Identifying the transcriptional control of ELOVL6 resolved how lipogenic signals converge on fatty acid elongation: SREBP-1c directly binds SRE elements in the Elovl6 promoter, placing ELOVL6 under the canonical lipogenic transcriptional program.","evidence":"Luciferase reporter, EMSA, ChIP, and adenoviral RNAi of SREBP-1 in mouse liver","pmids":["18226595"],"confidence":"High","gaps":["Contribution of other transcription factors (e.g., LXR, ChREBP) to ELOVL6 regulation not addressed","Post-transcriptional regulation mechanisms unknown at this point"]},{"year":2009,"claim":"A selective radioligand binding study provided the first pharmacological and mechanistic insight into the ELOVL6 active site, revealing that inhibitor binding requires the palmitoyl-CoA-bound enzyme state, consistent with an acyl-enzyme intermediate.","evidence":"Radioligand binding assay with palmitoyl-CoA dependence and selectivity profiling against ELOVL family members","pmids":["19505953"],"confidence":"Medium","gaps":["No structural model of the ELOVL6 active site or inhibitor binding mode","In vivo efficacy of selective inhibitors not demonstrated"]},{"year":2011,"claim":"Two studies demonstrated that ELOVL6 activity governs lipotoxic ER stress and cell death across distinct cell types: in β-cells, ELOVL6 drives palmitate-to-stearate conversion causing ER stress and apoptosis, while in macrophages ELOVL6 modulates cholesterol efflux and atherosclerotic lesion formation through altered esterified cholesterol fatty acid composition.","evidence":"siRNA knockdown and overexpression with radiolabeled fatty acid tracking in INS-1 cells; bone marrow transplantation of Elovl6−/− cells into LDLR−/− mice with cholesterol efflux assays","pmids":["21266672","21817094"],"confidence":"High","gaps":["Specific lipid species (ceramides, phospholipids) mediating ER stress in β-cells not identified","Whether macrophage effects are through membrane composition or signaling lipids unclear"]},{"year":2012,"claim":"ELOVL6 was positioned upstream of NLRP3 inflammasome activation, connecting fatty acid elongation to innate immune inflammatory signaling in the liver and establishing a mechanistic basis for ELOVL6's role in NASH pathogenesis.","evidence":"Elovl6 loss- and gain-of-function mouse models with NLRP3 inflammasome activation assays; human NASH liver samples","pmids":["22753171"],"confidence":"High","gaps":["Direct lipid species triggering NLRP3 activation not identified","Whether ELOVL6-NLRP3 axis operates in non-hepatic tissues unknown"]},{"year":2014,"claim":"Three advances refined the biochemical understanding of ELOVL6: definitive in vivo substrate specificity was established (C16:0→C18:0 is ELOVL6-specific; C16:1n-7→C18:1n-7 is not), KAR was identified as a physical and functional activator of ELOVL6 through both conformational and catalytic mechanisms, and ELOVL6 deficiency was shown to improve β-cell function via altered islet ATP/ADP ratios.","evidence":"KO mouse lipidomics confirming substrate specificity; in vitro reconstitution with purified ELOVL6 and KAR mutants; islet isolation and GSIS assays from Elovl6−/− mice","pmids":["25281760","25003994","24938128"],"confidence":"High","gaps":["Crystal structure of ELOVL6-KAR complex not available","Whether KAR interaction is specific to ELOVL6 or shared with other ELOVLs unknown","Mechanism linking fatty acid composition to ATP/ADP ratio in islets not resolved"]},{"year":2015,"claim":"ELOVL6 was shown to be essential for brown adipose tissue thermogenic function, linking fatty acid elongation to mitochondrial electron transport chain integrity and revealing compensatory white adipose tissue beiging in its absence.","evidence":"Elovl6 KO mice under cold exposure with BAT ETC component expression and oxygen consumption measurements","pmids":["26628376"],"confidence":"High","gaps":["Which specific lipid species are required for ETC complex assembly or function not defined","Whether BAT-specific ELOVL6 deletion recapitulates the phenotype unknown"]},{"year":2016,"claim":"ELOVL6 was connected to vascular smooth muscle cell phenotypic switching through a defined ROS→AMPK→KLF4 pathway, and separately to chondrocyte growth plate biology through altered transcription factor localization, broadening the known tissue contexts of ELOVL6 function.","evidence":"Elovl6−/− wire-injury model and VSMC siRNA with KLF4 epistasis; Elovl6 KO mouse skeletal analysis with chondrocyte knockdown","pmids":["27881420","27467521"],"confidence":"High","gaps":["How altered fatty acid composition generates ROS in VSMCs is mechanistically undefined","Direct lipid mediators affecting HDAC4/5/7 localization in chondrocytes not identified"]},{"year":2017,"claim":"Oleate (C18:1n-9) was identified as a key lipotoxic mediator downstream of ELOVL6 in pancreatic islets: Elovl6 deletion in diabetic db/db mice preserved β-cell mass by preventing oleate accumulation and associated ER stress, inflammation, and apoptosis.","evidence":"Elovl6 deletion in db/db mice; β-cell mass morphometry; ex vivo oleate treatment of isolated islets with GSIS and ER stress assays","pmids":["28461456"],"confidence":"High","gaps":["Whether oleate toxicity is direct or requires incorporation into ceramides/phospholipids unclear","Relevance to human β-cell lipotoxicity not confirmed"]},{"year":2018,"claim":"Studies in Drosophila and mouse keratinocytes extended ELOVL6's ER stress role across species and revealed tissue-specific consequences: loss of the Drosophila ortholog Baldspot rescued retinal degeneration by reducing IRE1/PERK signaling (rescued by dietary stearate), while in murine skin ELOVL6 deficiency caused cis-vaccenic acid accumulation driving DAMP release and proinflammatory responses.","evidence":"Drosophila Baldspot KO with Rh1G69D ER stress model and dietary stearate rescue; Elovl6−/− mouse tape-stripping model with epidermal lipidomics and DAMP measurement","pmids":["30081392","30518914"],"confidence":"Medium","gaps":["How stearate specifically alleviates ER stress at the molecular level not defined","Whether cis-vaccenic acid directly triggers cell death or acts through membrane perturbation unknown"]},{"year":2021,"claim":"ELOVL6 was placed within ceramide-dependent drug sensitivity and ferroptosis pathways: ELOVL6-dependent ceramide species are required for bortezomib-induced ER stress and cell death in myeloma, while ELOVL6 physically interacts with ACSL4 to modulate ferroptotic signaling in colorectal cancer; additionally, SREBP1 regulation of ELOVL6 through SRE elements was confirmed in a non-rodent mammalian system.","evidence":"ELOVL6 knockdown/overexpression in myeloma cells with lipidomics and xenograft; Co-IP of ELOVL6-ACSL4 with ferroptosis assays in HCT116 cells; ChIP and promoter mutagenesis in goat mammary epithelial cells","pmids":["33821992","33603479","33685712"],"confidence":"High","gaps":["ACSL4 interaction confirmed by single Co-IP only, no reciprocal validation","Specific ceramide species mediating BTZ sensitivity not individually tested","Whether ELOVL6-ACSL4 interaction is direct or mediated through a lipid intermediate unknown"]},{"year":2022,"claim":"ELOVL6 was positioned upstream of the ceramide–sphingosine-1-phosphate biosynthesis axis in airway immunity: Elovl6 deficiency aggravated allergic inflammation through elevated palmitic acid, ceramides, and S1P, which could be pharmacologically reversed by ceramide synthase or sphingosine kinase inhibitors.","evidence":"Elovl6−/− mouse ovalbumin and HDM asthma models with lung lipidomics and pharmacological epistasis","pmids":["36592705"],"confidence":"High","gaps":["Whether this ceramide-S1P axis operates similarly in other mucosal tissues unknown","Cell-type specificity (epithelial vs. immune) of ELOVL6 function in airway inflammation not resolved"]},{"year":2023,"claim":"ELOVL6 was shown to control macrophage inflammatory-to-reparative phenotype switching via S1P/PPARγ signaling, enhancing ABCA1-mediated lipid efflux and neurotrophic factor production, with functional consequences for demyelination and remyelination in neuroinflammatory disease models.","evidence":"Elovl6−/− macrophages with myelin phagocytosis, S1P/PPARγ pathway analysis, organotypic brain slices, and cuprizone mouse model","pmids":["37669365"],"confidence":"High","gaps":["Whether ELOVL6 modulation in microglia versus infiltrating macrophages produces distinct effects unknown","Therapeutic window and specificity of ELOVL6 targeting in neuroinflammation not defined"]},{"year":2025,"claim":"ELOVL6 was identified as a critical regulator of membrane phospholipid composition with direct consequences for oncogenic signaling: c-MYC-driven ELOVL6 upregulation in PDAC alters membrane rigidity and pinocytosis; ELOVL6 controls phosphatidylethanolamine levels required for mitochondrial OXPHOS in bladder cancer; and a genome-wide CRISPR screen identified ELOVL6 as essential for KRAS-G12V membrane association and protein stability through phospholipid production.","evidence":"PDAC mouse models with membrane property measurements; ELOVL6 siRNA in bladder cancer cells with lipidomics and mitochondrial assays; genome-wide CRISPR KO screen with phospholipidomics and KRAS protein degradation assays","pmids":["39956817","40835210","40954224"],"confidence":"High","gaps":["Specific phospholipid species required for KRAS-G12V membrane anchoring not individually defined","Whether ELOVL6 inhibition selectively targets mutant KRAS over wild-type KRAS in vivo unknown","Structural basis for how altered phospholipid composition affects membrane protein stability not resolved"]},{"year":null,"claim":"Key remaining questions include the structural basis of ELOVL6 catalysis and its interaction with KAR, the identity of specific lipid species mediating ELOVL6-dependent signaling in each tissue context, and whether ELOVL6 inhibition can be therapeutically exploited with acceptable metabolic safety.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of ELOVL6 or ELOVL6-KAR complex","Tissue-specific and cell-type-specific contributions of ELOVL6 not dissected with conditional knockouts in most contexts","Therapeutic index of ELOVL6 inhibition across metabolic, inflammatory, and oncologic settings not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,6,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8,22]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,8]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,6,8,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,10,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,17,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,12,16]}],"complexes":[],"partners":["KAR","SREBP1","ACSL4"],"other_free_text":[]},"mechanistic_narrative":"ELOVL6 is a microsomal fatty acid elongase that serves as the sole enzyme converting palmitate (C16:0) to stearate (C18:0) in vivo, thereby controlling the C16-to-C18 ratio of saturated and monounsaturated fatty acids and shaping the composition of downstream lipid species including ceramides, sphingolipids, and phospholipids [PMID:17906635, PMID:25281760]. Transcriptionally regulated by SREBP-1c through sterol regulatory elements in its promoter [PMID:18226595, PMID:33685712] and post-translationally activated by physical interaction with the 3-ketoacyl-CoA reductase KAR [PMID:25003994], ELOVL6 activity determines membrane lipid composition that in turn modulates insulin signaling via IRS-2/PKCε/Akt [PMID:17906635], ER stress through IRE1/PERK pathways and ceramide generation [PMID:21266672, PMID:30081392, PMID:33821992], NLRP3 inflammasome activation [PMID:22753171], and mitochondrial oxidative phosphorylation [PMID:26628376, PMID:40835210]. By governing fatty acid chain length, ELOVL6 broadly influences metabolic homeostasis, inflammatory responses, and cell fate decisions—including vascular smooth muscle phenotypic switching via ROS/AMPK/KLF4 [PMID:27881420], macrophage cholesterol efflux and repair phenotypes [PMID:21817094, PMID:37669365], phospholipid-dependent KRAS-G12V membrane association and stability [PMID:40954224], and membrane rigidity controlling pinocytosis in pancreatic cancer [PMID:39956817]."},"prefetch_data":{"uniprot":{"accession":"Q9H5J4","full_name":"Very long chain fatty acid elongase 6","aliases":["3-keto acyl-CoA synthase ELOVL6","ELOVL fatty acid elongase 6","ELOVL FA elongase 6","Elongation of very long chain fatty acids protein 6","Fatty acid elongase 2","hELO2","Fatty acyl-CoA elongase","Long-chain fatty-acyl elongase","Very long chain 3-ketoacyl-CoA synthase 6","Very long chain 3-oxoacyl-CoA synthase 6"],"length_aa":265,"mass_kda":31.4,"function":"Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. 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for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40913417","citation_count":1,"is_preprint":false},{"pmid":"27770615","id":"PMC_27770615","title":"Plesiomonas shigelloides exports a lethal cytotoxic-enterotoxin (LCE) by membrane vesicles.","date":"2016","source":"The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27770615","citation_count":1,"is_preprint":false},{"pmid":"40954224","id":"PMC_40954224","title":"ELOVL6 activity attenuation induces mutant KRAS degradation.","date":"2025","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/40954224","citation_count":1,"is_preprint":false},{"pmid":"39996802","id":"PMC_39996802","title":"Dietary Oleic Acid and SCD16 and ELOVL6 Estimated Activities Can Modify Erythrocyte Membrane n-3 and n-6 HUFA Partition: A Pilot Study.","date":"2025","source":"Current issues in molecular 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Loss of Elovl6 protects against obesity-induced insulin resistance by restoring hepatic insulin receptor substrate-2 (IRS-2) and suppressing hepatic protein kinase C epsilon (PKCε) activity, thereby restoring Akt phosphorylation.\",\n      \"method\": \"Elovl6 knockout mouse model; high-fat diet and ob/ob cross; measurement of hepatic fatty acid composition, IRS-2, PKCε activity, and Akt phosphorylation\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with multiple orthogonal biochemical readouts; foundational paper replicated widely\",\n      \"pmids\": [\"17906635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The mouse Elovl6 gene promoter is a direct transcriptional target of SREBP-1c; two sterol regulatory elements (SRE-1 and SRE-2) in the promoter bind SREBP, with SRE-1 having higher affinity; adenoviral RNAi knockdown of SREBP-1 in mouse liver suppresses Elovl6 mRNA.\",\n      \"method\": \"Luciferase reporter assay; EMSA; chromatin immunoprecipitation (ChIP); adenoviral RNAi in mouse liver\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (reporter assay, EMSA, ChIP, in vivo RNAi) in single study\",\n      \"pmids\": [\"18226595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ELOVL6 is a microsomal enzyme elongating C12–C16 saturated and monounsaturated fatty acids; in pancreatic β-cells, Elovl6 knockdown limits palmitate elongation to stearate and increases palmitoleate production, attenuating palmitate-induced ER stress and apoptosis; conversely, Elovl6 overexpression increases palmitate elongation to stearate and enhances ER stress and apoptosis.\",\n      \"method\": \"siRNA knockdown and overexpression in INS-1 β-cells; fatty acid radiolabeling to track elongation; measurement of ER stress markers and apoptosis\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with biochemical substrate tracking and multiple cellular readouts\",\n      \"pmids\": [\"21266672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Macrophage-specific Elovl6 deficiency reduces foam cell formation by increasing cholesterol efflux and expression of cholesterol efflux transporters; absence of Elovl6 decreases n-6 polyunsaturated fatty acids in the esterified cholesterol fraction of macrophages; bone marrow transplantation of Elovl6-/- cells into LDL-R-/- mice reduces atherosclerotic lesion area.\",\n      \"method\": \"Bone marrow transplantation into LDL-R-/- mice; peritoneal macrophage isolation; acetylated-LDL uptake and cholesterol efflux assays; fatty acid composition analysis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo bone marrow transplant plus multiple ex vivo mechanistic assays\",\n      \"pmids\": [\"21817094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Elovl6 promotes nonalcoholic steatohepatitis (NASH); deletion of Elovl6 reduces palmitate-induced activation of the NLRP3 inflammasome, which is a mechanistic basis for Elovl6-mediated modulation of hepatic inflammation, oxidative stress, and fibrosis.\",\n      \"method\": \"Elovl6 loss- and gain-of-function mouse models; NLRP3 inflammasome activation assays; human NASH liver samples for correlation\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — three independent mouse models plus in vitro inflammasome assays\",\n      \"pmids\": [\"22753171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Elovl6 is a rate-limiting enzyme for elongation of saturated and monounsaturated fatty acids; its deficiency in mice causes derangement of fatty acid profile and leads to severe fibroproliferative response after bleomycin-induced lung injury; Elovl6 knockdown induces apoptosis, TGF-β1 expression, and reactive oxygen species generation in alveolar type II epithelial cells.\",\n      \"method\": \"Elovl6-/- mouse model with intratracheal bleomycin; siRNA knockdown in lung epithelial cells; measurement of apoptosis, TGF-β1, and ROS\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse phenotype plus in vitro knockdown with multiple mechanistic readouts\",\n      \"pmids\": [\"24113622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ELOVL6 is the only enzyme capable of elongating palmitate (C16:0) to stearate (C18:0) in vivo; Elovl6-/- mouse livers accumulate C16:0 and C16:1 n-7 with loss of C18:0 and C18:1 n-9, confirming substrate specificity. Palmitoleate (C16:1 n-7) to vaccenate (C18:1 n-7) elongation was not specific to ELOVL6.\",\n      \"method\": \"Elovl6 knockout mouse generation; hepatic fatty acid composition analysis by mass spectrometry; dietary intervention studies\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — definitive substrate specificity established by KO + detailed lipidomics in vivo\",\n      \"pmids\": [\"25281760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ELOVL6 activity regulates fatty acid composition in pancreatic islets; in Elovl6-/- mice fed a high-fat/high-sucrose diet, improved glucose-stimulated insulin secretion (GSIS) is associated with increased islet ATP/ADP ratio and suppression of ATF-3 expression.\",\n      \"method\": \"Elovl6-/- mouse model; high-fat/high-sucrose diet; isolated islet glucose-stimulated insulin secretion assay; ATP/ADP ratio measurement; ATF-3 expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype, but single lab single study\",\n      \"pmids\": [\"24938128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ELOVL6 enzymatic activity is regulated by the 3-ketoacyl-CoA reductase KAR via two modes: (1) KAR induces conformational changes in ELOVL6 independent of KAR enzyme activity, enhancing ELOVL6 activity ~3-fold; (2) KAR enzyme activity-dependent conversion of 3-ketoacyl-CoA to 3-hydroxyacyl-CoA facilitates product release from a presumed ELOVL6-KAR complex, further enhancing activity ~10-fold in the presence of NADPH.\",\n      \"method\": \"In vitro fatty acid elongation assay using membrane fractions; purified ELOVL6; KAR mutants; NADPH-dependence experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with purified proteins and mutagenesis\",\n      \"pmids\": [\"25003994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Elovl6 is necessary for thermogenic function of brown adipose tissue (BAT); loss of Elovl6 causes reduced expression of mitochondrial electron transport chain components and lower BAT thermogenic capacity without altering classical BAT markers; this is compensated by increased beiging of subcutaneous white adipose tissue.\",\n      \"method\": \"Elovl6 KO mice; cold exposure experiments; mitochondrial ETC component expression; BAT oxygen consumption; thermoneutrality and aging studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple physiological and molecular readouts across multiple conditions\",\n      \"pmids\": [\"26628376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Elovl6 inhibition in vascular smooth muscle cells (VSMCs) causes increased palmitate and reduced oleate levels, leading to ROS production, AMPK activation, induction of KLF4 (a pluripotency gene), and phenotypic switching of VSMCs including growth arrest and downregulation of VSMC markers; KLF4 knockdown attenuates AMPK-induced phenotypic switching, establishing KLF4 as a bona fide AMPK target in this pathway.\",\n      \"method\": \"Elovl6-/- mouse neointima wire-injury model; siRNA knockdown in cultured VSMCs; PDGF-BB stimulation; ROS measurement; AMPK and mTOR phosphorylation; KLF4 knockdown epistasis\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO phenotype plus in vitro mechanistic pathway dissection with epistasis experiment\",\n      \"pmids\": [\"27881420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Elovl6 plays a critical role in chondrocyte growth and differentiation during growth plate development; Elovl6-/- mice show reduced chondrocyte proliferation and accelerated hypertrophic differentiation, associated with increased Collagen10α1 expression and elevated Foxa2/a3 and Mef2c mRNA; increased nuclear Foxa2 and cytoplasmic HDAC4/5/7 protein levels are observed in Elovl6 knockdown chondrocytes.\",\n      \"method\": \"Elovl6 KO mouse skeletal analysis; histology; gene expression; siRNA knockdown in chondrocyte cell lines; protein localization by fractionation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse phenotype plus in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"27467521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Elovl6 deletion in db/db mice markedly increases β-cell mass with increased proliferation and decreased apoptosis; Elovl6 deletion suppresses oleate (C18:1n-9) elevation in islets, cell stress, and inflammation; isolated Elovl6-/- islets show reduced susceptibility to palmitate-induced ER stress, inflammation, and β-cell apoptosis; oleate-treated islets impair glucose-stimulated insulin secretion regardless of Elovl6 genotype, implicating oleate as a key lipotoxic mediator.\",\n      \"method\": \"Elovl6 deletion in db/db mouse model; β-cell mass morphometry; islet isolation; ex vivo palmitate and oleate treatment; ER stress markers; GSIS assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model plus multiple ex vivo mechanistic experiments with clear pathway placement\",\n      \"pmids\": [\"28461456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Elovl6 in keratinocytes regulates fatty acid composition; Elovl6-/- mice have higher levels of cis-vaccenic acid (CVA) in the epidermis; CVA accelerates tape stripping-triggered keratinocyte death and release of DAMPs (HMGB-1 and IL-1α), which induce proinflammatory cytokine and chemokine production (IL-1β, CXCL-1).\",\n      \"method\": \"Elovl6-/- mouse tape-stripping model; epidermal fatty acid composition analysis; DAMP measurement; cytokine/chemokine quantification\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with mechanistic follow-up, single lab\",\n      \"pmids\": [\"30518914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In a Drosophila model (Baldspot/ELOVL6 ortholog), loss of Baldspot rescues retinal degeneration in a model of ER stress (Rh1G69D) and reduces IRE1 and PERK signaling and cell death; dietary supplementation with stearate bypasses the need for Baldspot activity, linking the enzyme's conversion of C16 to C18 to ER stress modulation.\",\n      \"method\": \"Drosophila Baldspot knockout; Rh1G69D ER stress model; IRE1 and PERK signaling assays; dietary stearate supplementation rescue\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ortholog genetic model with epistasis and dietary rescue, single lab\",\n      \"pmids\": [\"30081392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL6 directly interacts with ACSL4 (a key regulator of ferroptosis), as confirmed by co-immunoprecipitation; ELOVL6 overexpression in colorectal cancer HCT116 cells reverses apatinib-induced ferroptosis, indicating ELOVL6 acts upstream of ACSL4-mediated ferroptotic signaling.\",\n      \"method\": \"Co-immunoprecipitation; ELOVL6 overexpression; CCK-8 cell viability; ROS and iron measurement; Western blot for ferroptosis markers\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional overexpression data, single lab\",\n      \"pmids\": [\"33603479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL6 levels regulate bortezomib (BTZ) sensitivity in multiple myeloma cells; ELOVL6 depletion suppresses BTZ-induced ER stress and cytotoxicity; restoration of ELOVL6 in BTZ-resistant cells resensitizes them to BTZ via upregulation of ELOVL6-dependent ceramide species, which are required for BTZ-induced ER stress and cell death.\",\n      \"method\": \"ELOVL6 knockdown and overexpression in MM cell lines; BTZ treatment; lipidomic profiling; ceramide measurement; xenograft plasmacytoma mouse model\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (lipidomics, in vitro gain/loss of function, in vivo xenograft) in single study\",\n      \"pmids\": [\"33821992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELOVL6 deficiency in mice aggravates allergic airway inflammation; lipidomic profiling revealed elevated palmitic acid, ceramides, and sphingosine-1-phosphate (S1P) in Elovl6-/- mouse lungs after sensitization; treatment with inhibitors of ceramide synthase (fumonisin B1) or sphingosine kinase (DL-threo-dihydrosphingosine) ameliorated the aggravated inflammation, placing ELOVL6 upstream of the ceramide-S1P biosynthesis pathway in airway immune regulation.\",\n      \"method\": \"Elovl6-/- mouse ovalbumin and house dust mite asthma models; lipidomic profiling; pharmacological inhibition of ceramide synthase and sphingosine kinase; cellular immunology assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with lipidomics and pharmacological epistasis establishing pathway mechanism\",\n      \"pmids\": [\"36592705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELOVL6 is upregulated in myelin-phagocytosing macrophages and in MS lesions; Elovl6 depletion induces a repair-promoting phagocyte phenotype through activation of the S1P/PPARγ pathway, enhances ABCA1-mediated lipid efflux, increases neurotrophic factor production, and reduces inflammatory mediator expression; Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the cuprizone mouse model.\",\n      \"method\": \"In vitro myelin phagocytosis model; Elovl6-/- macrophages; S1P/PPARγ pathway analysis; ABCA1-mediated cholesterol efflux assay; organotypic brain slice cultures; cuprizone mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro and in vivo models with defined molecular pathway\",\n      \"pmids\": [\"37669365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-135b-5p, miR-135a-5p, miR-125a-5p, miR-125b-5p, and miR-22-3p directly bind the 3'-UTR of human ELOVL6 mRNA and downregulate its expression; miR-135b-5p and miR-135a-5p suppress glioblastoma cell proliferation and migration by inhibiting ELOVL6 at both mRNA and protein levels.\",\n      \"method\": \"Dual-luciferase reporter assay with ELOVL6 3'-UTR; miRNA overexpression in glioblastoma cells; cell proliferation and migration assays; qRT-PCR and Western blot\",\n      \"journal\": \"BBA advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter plus functional cellular assays, single lab\",\n      \"pmids\": [\"37082255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"c-MYC directly upregulates ELOVL6 expression during pancreatic cancer (PDAC) tumor progression; genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability, and pinocytosis; in vivo ELOVL6 inhibition suppresses tumor growth and improves Abraxane response.\",\n      \"method\": \"PDAC mouse models and cell lines; c-MYC overexpression/inhibition; ELOVL6 genetic knockdown and chemical inhibitor; fatty acid composition analysis; membrane property measurements; in vivo tumor growth and survival\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo models with defined molecular mechanism and pathway placement\",\n      \"pmids\": [\"39956817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL6 controls phospholipid production exploited by KRAS-G12V for membrane association; CRISPR-Cas9 genome-wide knockout screen identified ELOVL6 as a selective modulator of KRAS-G12V protein expression; ELOVL6 attenuation induces degradation of KRAS-G12V protein through altered phospholipid composition, reducing aberrant oncogenic signaling.\",\n      \"method\": \"CRISPR-Cas9 genome-wide KO screen; ELOVL6 inhibition in KRAS-G12V cancer cells; phospholipidomics; KRAS protein expression and degradation assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide functional screen plus lipidomics and protein degradation mechanism, single study\",\n      \"pmids\": [\"40954224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A selective radioligand ([(3)H]Compound-A) was identified for ELOVL6 that binds in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH, suggesting Compound-A recognizes an enzyme-substrate (acyl-enzyme intermediate) complex; Compound-A inhibits human and mouse ELOVL6 with >100-fold selectivity over other ELOVL family members.\",\n      \"method\": \"Radioligand binding assay; enzyme inhibition assay; selectivity profiling against ELOVL family members; substrate-dependence studies\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical binding and inhibition assays with mechanistic inference about active site, single lab\",\n      \"pmids\": [\"19505953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL6 knockdown in FGFR3-mutant bladder cancer cells markedly reduces phosphatidylethanolamine levels, impairs mitochondrial complex I and II protein expression and mitochondrial oxidative phosphorylation (OXPHOS), and activates the ECM-integrin-FAK pathway as a compensatory response; these data establish that ELOVL6 regulates lipid composition to preserve mitochondrial function.\",\n      \"method\": \"ELOVL6 siRNA knockdown in BC cell lines; lipidomics; mitochondrial OXPHOS measurement; RNA sequencing; in vivo tumor growth\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — lipidomics plus functional mitochondrial assays with transcriptomics, single lab\",\n      \"pmids\": [\"40835210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP1 directly binds to SRE1 and SRE3 elements in the goat ELOVL6 promoter to regulate its transcription; mutation of both SRE sites abolishes SREBP1-stimulated and linoleic acid-repressed ELOVL6 promoter activity; chromatin immunoprecipitation confirmed in vivo SREBP1 binding at these sites in goat mammary epithelial cells.\",\n      \"method\": \"Promoter deletion analysis; site-directed mutagenesis; luciferase reporter assay; chromatin immunoprecipitation in goat mammary epithelial cells\",\n      \"journal\": \"Journal of dairy science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal promoter analyses in a non-rodent mammalian system, single lab\",\n      \"pmids\": [\"33685712\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELOVL6 is a microsomal fatty acid elongase that catalyzes the rate-limiting condensation step converting C16 saturated and monounsaturated fatty acids (palmitate, palmitoleate) to their C18 counterparts (stearate, oleate), a reaction directly regulated at the transcriptional level by SREBP-1c binding to SRE elements in the promoter; its enzymatic activity is further modulated post-translationally by physical interaction with the downstream elongation cycle enzyme KAR, which enhances ELOVL6 activity both through conformational change and via product-release facilitation; by controlling the C16/C18 fatty acid balance, ELOVL6 shapes membrane lipid composition (including ceramide and phospholipid species) to regulate insulin signaling (via IRS-2 and PKCε/Akt), NLRP3 inflammasome activation, ER stress responses (via IRE1/PERK and ceramide), mitochondrial function, and VSMC phenotypic switching (via ROS/AMPK/KLF4), establishing cellular fatty acid composition as a broadly important determinant of metabolic and inflammatory homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ELOVL6 is a microsomal fatty acid elongase that serves as the sole enzyme converting palmitate (C16:0) to stearate (C18:0) in vivo, thereby controlling the C16-to-C18 ratio of saturated and monounsaturated fatty acids and shaping the composition of downstream lipid species including ceramides, sphingolipids, and phospholipids [PMID:17906635, PMID:25281760]. Transcriptionally regulated by SREBP-1c through sterol regulatory elements in its promoter [PMID:18226595, PMID:33685712] and post-translationally activated by physical interaction with the 3-ketoacyl-CoA reductase KAR [PMID:25003994], ELOVL6 activity determines membrane lipid composition that in turn modulates insulin signaling via IRS-2/PKCε/Akt [PMID:17906635], ER stress through IRE1/PERK pathways and ceramide generation [PMID:21266672, PMID:30081392, PMID:33821992], NLRP3 inflammasome activation [PMID:22753171], and mitochondrial oxidative phosphorylation [PMID:26628376, PMID:40835210]. By governing fatty acid chain length, ELOVL6 broadly influences metabolic homeostasis, inflammatory responses, and cell fate decisions—including vascular smooth muscle phenotypic switching via ROS/AMPK/KLF4 [PMID:27881420], macrophage cholesterol efflux and repair phenotypes [PMID:21817094, PMID:37669365], phospholipid-dependent KRAS-G12V membrane association and stability [PMID:40954224], and membrane rigidity controlling pinocytosis in pancreatic cancer [PMID:39956817].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing the core enzymatic function of ELOVL6 and its metabolic significance: the foundational question of which elongase converts C16:0 to C18:0 was resolved, revealing that ELOVL6 loss protects against obesity-induced insulin resistance by modulating hepatic PKCε/IRS-2/Akt signaling.\",\n      \"evidence\": \"Elovl6 knockout mouse on high-fat diet and ob/ob background with hepatic fatty acid profiling and insulin signaling readouts\",\n      \"pmids\": [\"17906635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Substrate specificity among other chain lengths and unsaturated species not fully delineated\",\n        \"Whether protection from insulin resistance is cell-autonomous in hepatocytes versus systemic\",\n        \"Mechanism linking altered C16/C18 ratio to PKCε activity not defined\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying the transcriptional control of ELOVL6 resolved how lipogenic signals converge on fatty acid elongation: SREBP-1c directly binds SRE elements in the Elovl6 promoter, placing ELOVL6 under the canonical lipogenic transcriptional program.\",\n      \"evidence\": \"Luciferase reporter, EMSA, ChIP, and adenoviral RNAi of SREBP-1 in mouse liver\",\n      \"pmids\": [\"18226595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Contribution of other transcription factors (e.g., LXR, ChREBP) to ELOVL6 regulation not addressed\",\n        \"Post-transcriptional regulation mechanisms unknown at this point\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A selective radioligand binding study provided the first pharmacological and mechanistic insight into the ELOVL6 active site, revealing that inhibitor binding requires the palmitoyl-CoA-bound enzyme state, consistent with an acyl-enzyme intermediate.\",\n      \"evidence\": \"Radioligand binding assay with palmitoyl-CoA dependence and selectivity profiling against ELOVL family members\",\n      \"pmids\": [\"19505953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the ELOVL6 active site or inhibitor binding mode\",\n        \"In vivo efficacy of selective inhibitors not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two studies demonstrated that ELOVL6 activity governs lipotoxic ER stress and cell death across distinct cell types: in β-cells, ELOVL6 drives palmitate-to-stearate conversion causing ER stress and apoptosis, while in macrophages ELOVL6 modulates cholesterol efflux and atherosclerotic lesion formation through altered esterified cholesterol fatty acid composition.\",\n      \"evidence\": \"siRNA knockdown and overexpression with radiolabeled fatty acid tracking in INS-1 cells; bone marrow transplantation of Elovl6−/− cells into LDLR−/− mice with cholesterol efflux assays\",\n      \"pmids\": [\"21266672\", \"21817094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific lipid species (ceramides, phospholipids) mediating ER stress in β-cells not identified\",\n        \"Whether macrophage effects are through membrane composition or signaling lipids unclear\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ELOVL6 was positioned upstream of NLRP3 inflammasome activation, connecting fatty acid elongation to innate immune inflammatory signaling in the liver and establishing a mechanistic basis for ELOVL6's role in NASH pathogenesis.\",\n      \"evidence\": \"Elovl6 loss- and gain-of-function mouse models with NLRP3 inflammasome activation assays; human NASH liver samples\",\n      \"pmids\": [\"22753171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct lipid species triggering NLRP3 activation not identified\",\n        \"Whether ELOVL6-NLRP3 axis operates in non-hepatic tissues unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Three advances refined the biochemical understanding of ELOVL6: definitive in vivo substrate specificity was established (C16:0→C18:0 is ELOVL6-specific; C16:1n-7→C18:1n-7 is not), KAR was identified as a physical and functional activator of ELOVL6 through both conformational and catalytic mechanisms, and ELOVL6 deficiency was shown to improve β-cell function via altered islet ATP/ADP ratios.\",\n      \"evidence\": \"KO mouse lipidomics confirming substrate specificity; in vitro reconstitution with purified ELOVL6 and KAR mutants; islet isolation and GSIS assays from Elovl6−/− mice\",\n      \"pmids\": [\"25281760\", \"25003994\", \"24938128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crystal structure of ELOVL6-KAR complex not available\",\n        \"Whether KAR interaction is specific to ELOVL6 or shared with other ELOVLs unknown\",\n        \"Mechanism linking fatty acid composition to ATP/ADP ratio in islets not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ELOVL6 was shown to be essential for brown adipose tissue thermogenic function, linking fatty acid elongation to mitochondrial electron transport chain integrity and revealing compensatory white adipose tissue beiging in its absence.\",\n      \"evidence\": \"Elovl6 KO mice under cold exposure with BAT ETC component expression and oxygen consumption measurements\",\n      \"pmids\": [\"26628376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific lipid species are required for ETC complex assembly or function not defined\",\n        \"Whether BAT-specific ELOVL6 deletion recapitulates the phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"ELOVL6 was connected to vascular smooth muscle cell phenotypic switching through a defined ROS→AMPK→KLF4 pathway, and separately to chondrocyte growth plate biology through altered transcription factor localization, broadening the known tissue contexts of ELOVL6 function.\",\n      \"evidence\": \"Elovl6−/− wire-injury model and VSMC siRNA with KLF4 epistasis; Elovl6 KO mouse skeletal analysis with chondrocyte knockdown\",\n      \"pmids\": [\"27881420\", \"27467521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How altered fatty acid composition generates ROS in VSMCs is mechanistically undefined\",\n        \"Direct lipid mediators affecting HDAC4/5/7 localization in chondrocytes not identified\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Oleate (C18:1n-9) was identified as a key lipotoxic mediator downstream of ELOVL6 in pancreatic islets: Elovl6 deletion in diabetic db/db mice preserved β-cell mass by preventing oleate accumulation and associated ER stress, inflammation, and apoptosis.\",\n      \"evidence\": \"Elovl6 deletion in db/db mice; β-cell mass morphometry; ex vivo oleate treatment of isolated islets with GSIS and ER stress assays\",\n      \"pmids\": [\"28461456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether oleate toxicity is direct or requires incorporation into ceramides/phospholipids unclear\",\n        \"Relevance to human β-cell lipotoxicity not confirmed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Studies in Drosophila and mouse keratinocytes extended ELOVL6's ER stress role across species and revealed tissue-specific consequences: loss of the Drosophila ortholog Baldspot rescued retinal degeneration by reducing IRE1/PERK signaling (rescued by dietary stearate), while in murine skin ELOVL6 deficiency caused cis-vaccenic acid accumulation driving DAMP release and proinflammatory responses.\",\n      \"evidence\": \"Drosophila Baldspot KO with Rh1G69D ER stress model and dietary stearate rescue; Elovl6−/− mouse tape-stripping model with epidermal lipidomics and DAMP measurement\",\n      \"pmids\": [\"30081392\", \"30518914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How stearate specifically alleviates ER stress at the molecular level not defined\",\n        \"Whether cis-vaccenic acid directly triggers cell death or acts through membrane perturbation unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ELOVL6 was placed within ceramide-dependent drug sensitivity and ferroptosis pathways: ELOVL6-dependent ceramide species are required for bortezomib-induced ER stress and cell death in myeloma, while ELOVL6 physically interacts with ACSL4 to modulate ferroptotic signaling in colorectal cancer; additionally, SREBP1 regulation of ELOVL6 through SRE elements was confirmed in a non-rodent mammalian system.\",\n      \"evidence\": \"ELOVL6 knockdown/overexpression in myeloma cells with lipidomics and xenograft; Co-IP of ELOVL6-ACSL4 with ferroptosis assays in HCT116 cells; ChIP and promoter mutagenesis in goat mammary epithelial cells\",\n      \"pmids\": [\"33821992\", \"33603479\", \"33685712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"ACSL4 interaction confirmed by single Co-IP only, no reciprocal validation\",\n        \"Specific ceramide species mediating BTZ sensitivity not individually tested\",\n        \"Whether ELOVL6-ACSL4 interaction is direct or mediated through a lipid intermediate unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ELOVL6 was positioned upstream of the ceramide–sphingosine-1-phosphate biosynthesis axis in airway immunity: Elovl6 deficiency aggravated allergic inflammation through elevated palmitic acid, ceramides, and S1P, which could be pharmacologically reversed by ceramide synthase or sphingosine kinase inhibitors.\",\n      \"evidence\": \"Elovl6−/− mouse ovalbumin and HDM asthma models with lung lipidomics and pharmacological epistasis\",\n      \"pmids\": [\"36592705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this ceramide-S1P axis operates similarly in other mucosal tissues unknown\",\n        \"Cell-type specificity (epithelial vs. immune) of ELOVL6 function in airway inflammation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ELOVL6 was shown to control macrophage inflammatory-to-reparative phenotype switching via S1P/PPARγ signaling, enhancing ABCA1-mediated lipid efflux and neurotrophic factor production, with functional consequences for demyelination and remyelination in neuroinflammatory disease models.\",\n      \"evidence\": \"Elovl6−/− macrophages with myelin phagocytosis, S1P/PPARγ pathway analysis, organotypic brain slices, and cuprizone mouse model\",\n      \"pmids\": [\"37669365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ELOVL6 modulation in microglia versus infiltrating macrophages produces distinct effects unknown\",\n        \"Therapeutic window and specificity of ELOVL6 targeting in neuroinflammation not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ELOVL6 was identified as a critical regulator of membrane phospholipid composition with direct consequences for oncogenic signaling: c-MYC-driven ELOVL6 upregulation in PDAC alters membrane rigidity and pinocytosis; ELOVL6 controls phosphatidylethanolamine levels required for mitochondrial OXPHOS in bladder cancer; and a genome-wide CRISPR screen identified ELOVL6 as essential for KRAS-G12V membrane association and protein stability through phospholipid production.\",\n      \"evidence\": \"PDAC mouse models with membrane property measurements; ELOVL6 siRNA in bladder cancer cells with lipidomics and mitochondrial assays; genome-wide CRISPR KO screen with phospholipidomics and KRAS protein degradation assays\",\n      \"pmids\": [\"39956817\", \"40835210\", \"40954224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific phospholipid species required for KRAS-G12V membrane anchoring not individually defined\",\n        \"Whether ELOVL6 inhibition selectively targets mutant KRAS over wild-type KRAS in vivo unknown\",\n        \"Structural basis for how altered phospholipid composition affects membrane protein stability not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key remaining questions include the structural basis of ELOVL6 catalysis and its interaction with KAR, the identity of specific lipid species mediating ELOVL6-dependent signaling in each tissue context, and whether ELOVL6 inhibition can be therapeutically exploited with acceptable metabolic safety.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of ELOVL6 or ELOVL6-KAR complex\",\n        \"Tissue-specific and cell-type-specific contributions of ELOVL6 not dissected with conditional knockouts in most contexts\",\n        \"Therapeutic index of ELOVL6 inhibition across metabolic, inflammatory, and oncologic settings not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 6, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 6, 8, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 10, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 17, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 12, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KAR\",\n      \"SREBP1\",\n      \"ACSL4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}