{"gene":"ELOVL6","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2007,"finding":"ELOVL6 is the microsomal elongase that catalyzes the conversion of palmitate (C16:0) to stearate (C18:0). Elovl6-knockout mice become obese and develop hepatosteatosis on high-fat diet but are markedly protected from hyperinsulinemia and hyperglycemia. The mechanism involves restoration of hepatic insulin receptor substrate-2 (IRS-2) and suppression of hepatic protein kinase C epsilon (PKCε) activity, resulting in restoration of Akt phosphorylation.","method":"Elovl6 knockout mouse model; high-fat diet and ob/ob mouse crosses; measurement of hepatic fatty acid composition, IRS-2, PKCε activity, and Akt phosphorylation","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular phenotype (PKCε suppression, IRS-2 restoration, Akt phosphorylation) replicated in two independent obese mouse models; foundational paper widely replicated","pmids":["17906635"],"is_preprint":false},{"year":2008,"finding":"The mouse Elovl6 gene promoter is a direct transcriptional target of SREBP-1c. Two SREBP binding sites (proximal SRE-1 and distal SRE-2) were identified, with SRE-1 showing higher affinity. SREBP-1c binds the Elovl6 promoter in vivo, and adenoviral RNAi knockdown of SREBP-1 in mouse liver suppresses Elovl6 mRNA.","method":"Luciferase reporter assays, EMSA, chromatin immunoprecipitation (ChIP), adenoviral RNAi knockdown in mouse liver","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, EMSA, ChIP, in vivo knockdown) in a single study; later replicated in goat mammary cells (PMID 33685712)","pmids":["18226595"],"is_preprint":false},{"year":2009,"finding":"A selective inhibitor (Compound A, an indoledione) was identified that potently inhibits human and mouse ELOVL6 with >100-fold selectivity over other ELOVL family members. A tritiated form ([³H]Compound-A) binds ELOVL6 in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH, suggesting it recognizes an acyl-enzyme intermediate.","method":"Biochemical inhibition assay; radioligand binding assay with [³H]Compound-A; selectivity profiling across ELOVL family members","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzyme assay with selective chemical probe and radioligand binding; single lab, single paper","pmids":["19505953"],"is_preprint":false},{"year":2010,"finding":"A novel orally active ELOVL6 inhibitor (Compound B) was developed that effectively inhibits ELOVL6 activity in vivo in diet-induced obese and KKAy mice, significantly reducing hepatic fatty acid composition. However, no improvement in insulin resistance was observed in these chronic pharmacological studies.","method":"In vivo chronic dosing of selective ELOVL6 inhibitor in DIO and KKAy mice; hepatic fatty acid composition analysis; insulin resistance measurement","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological tool in two in vivo models; single lab; negative result for insulin resistance is explicitly noted","pmids":["20045404"],"is_preprint":false},{"year":2011,"finding":"ELOVL6 in macrophages promotes foam cell formation and atherosclerosis. Elovl6-deficient macrophages accumulate less esterified cholesterol upon acetylated-LDL exposure, show increased cholesterol efflux and upregulated cholesterol efflux transporters, and bone marrow transplantation of Elovl6−/− cells into LDL-R−/− mice results in significantly smaller aortic atherosclerotic lesions.","method":"Bone marrow transplantation into irradiated LDL-R−/− mice; cholesterol efflux assay; fatty acid composition analysis of esterified cholesterol fraction in macrophages","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo bone marrow transplant plus ex vivo macrophage cholesterol efflux assays; multiple orthogonal methods in a single study","pmids":["21817094"],"is_preprint":false},{"year":2011,"finding":"ELOVL6 overexpression in pancreatic β-cells (INS-1) increases palmitate elongation to stearate and increases palmitate-induced ER stress and apoptosis, whereas ELOVL6 knockdown limits palmitate elongation and attenuates ER stress and apoptosis. This establishes ELOVL6 activity as a determinant of saturated fatty acid lipotoxicity in β-cells.","method":"Overexpression and RNAi knockdown in INS-1 cells; fatty acid profiling; ER stress and apoptosis assays","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in cell model with lipid and cell-death readouts; single lab","pmids":["21266672"],"is_preprint":false},{"year":2012,"finding":"ELOVL6 is a critical modulator of nonalcoholic steatohepatitis (NASH). Using three independent mouse models (loss and gain of function), deletion of Elovl6 reduces atherogenic diet-induced hepatic inflammation, oxidative stress, and fibrosis. Mechanistically, deletion of Elovl6 reduces palmitate-induced activation of the NLRP3 inflammasome.","method":"Elovl6 knockout and adenoviral overexpression mouse models; NASH dietary challenge; NLRP3 inflammasome activation assays; human NASH liver samples for expression correlation","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent mouse models (KO plus gain-of-function) with mechanistic NLRP3 inflammasome readout; multiple orthogonal approaches","pmids":["22753171"],"is_preprint":false},{"year":2013,"finding":"ELOVL6 is the only enzyme capable of elongating palmitate (C16:0) to stearate (C18:0); Elovl6−/− mice accumulate palmitic and palmitoleic acids and are severely depleted of stearic and oleic acids. Unexpectedly, palmitoleate (C16:1 n-7) elongation to vaccenate (C18:1 n-7) was not specific to ELOVL6. Deletion of ELOVL6 did not protect mice from obesity, fatty liver, hyperglycemia, or hyperinsulinemia on a high-fat diet or in ob/ob background (contradicting PMID 17906635 in some respects).","method":"Elovl6 knockout mouse generation; high-fat diet and ob/ob crosses; detailed hepatic fatty acid profiling by mass spectrometry","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — independent KO mouse line with comprehensive lipidomics; contradicts insulin-resistance protection finding from PMID 17906635","pmids":["25281760"],"is_preprint":false},{"year":2013,"finding":"Loss of Elovl6 in alveolar type II epithelial cells causes derangement of fatty acid profile, induces apoptosis, TGF-β1 expression, and reactive oxygen species generation; Elovl6-deficient mice exhibit severe fibroproliferative response to bleomycin, establishing a role for ELOVL6 in maintaining lung homeostasis.","method":"Elovl6 knockout mouse + bleomycin intratracheal instillation model; Elovl6 siRNA knockdown in cells; fatty acid profiling; apoptosis and ROS assays; TGF-β1 measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model combined with siRNA knockdown, multiple mechanistic readouts (apoptosis, ROS, TGF-β1); replicated across in vivo and in vitro systems","pmids":["24113622"],"is_preprint":false},{"year":2014,"finding":"KAR (3-ketoacyl-CoA reductase), which catalyzes the second step of the FA elongation cycle, regulates ELOVL6 via two modes: (1) a KAR enzyme activity-independent mode in which KAR protein induces conformational changes in ELOVL6 (~3-fold activity enhancement), and (2) a KAR enzyme activity-dependent mode in which conversion of 3-ketoacyl-CoA to 3-hydroxyacyl-CoA facilitates product release from a presumed ELOVL6-KAR complex, further enhancing ELOVL6 activity (~10-fold with NADPH present).","method":"In vitro FA elongation assays using membrane fractions; purified ELOVL6 activity assay with wild-type and catalytically dead KAR mutants; NADPH dependence experiments","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted enzymatic assay with active-site KAR mutant dissecting two mechanistic modes; single lab but rigorous biochemistry","pmids":["25003994"],"is_preprint":false},{"year":2014,"finding":"Elovl6 ablation protects pancreatic islets from high-fat/high-sucrose diet-induced impairment: Elovl6−/− islets show increased glucose-stimulated insulin secretion (GSIS) associated with an increased ATP/ADP ratio and suppression of ATF-3 expression, indicating Elovl6 affects insulin secretory capacity per β-cell.","method":"Elovl6 knockout mouse; HFHS diet challenge; islet GSIS measurement; ATP/ADP ratio; ATF-3 expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined β-cell functional readouts; single lab, single paper","pmids":["24938128"],"is_preprint":false},{"year":2015,"finding":"Elovl6 is necessary for brown adipose tissue (BAT) thermogenic capacity. Loss of Elovl6 does not alter canonical BAT markers but reduces expression of mitochondrial electron transport chain components and lowers BAT thermogenic capacity, converting C16 to C18 fatty acid species being required for full thermogenic function.","method":"Elovl6 knockout mice; cold exposure; mitochondrial ETC component expression; BAT thermogenesis measurement; thermoneutrality and aging experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple functional readouts (ETC expression, thermogenesis capacity); single lab","pmids":["26628376"],"is_preprint":false},{"year":2016,"finding":"Elovl6 inhibition in vascular smooth muscle cells (VSMCs) induces phenotypic switching via ROS production and AMPK/KLF4 signaling. Reduced oleate and increased palmitate from Elovl6 deficiency lead to ROS production, AMPK activation, induction of p53/p21, reduced mTOR phosphorylation, and robust KLF4 induction. KLF4 knockdown attenuates AMPK-induced phenotypic switching, identifying KLF4 as a bona fide AMPK target. Elovl6-null mice show markedly inhibited neointima formation after wire injury.","method":"Elovl6−/− mice with wire injury model; siRNA knockdown in VSMCs; PDGF-BB stimulation; ROS measurement; AMPK, mTOR phosphorylation; KLF4 KD epistasis","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo neointima model plus in vitro epistasis (KLF4 KD) with multiple signaling readouts; multiple orthogonal methods","pmids":["27881420"],"is_preprint":false},{"year":2016,"finding":"Elovl6 plays a crucial role in chondrocyte growth and differentiation during growth plate development. Elovl6-null mice have reduced proliferating chondrocyte layer, elongated hypertrophic zone, and decreased trabecular bone. Elovl6 ablation elevates Collagen10α1 expression, associated with increased Foxa2/a3 and Mef2c mRNA and elevated nuclear Foxa2 and cytoplasmic HDAC4/5/7 protein levels.","method":"Elovl6 knockout mice; skeletal histology; gene expression analysis; protein level measurement of Foxa2, HDAC4/5/7 in chondrocytes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with histological and molecular mechanistic readouts in chondrocytes; single lab","pmids":["27467521"],"is_preprint":false},{"year":2017,"finding":"In db/db mice (T2D model), Elovl6 deletion markedly increases β-cell mass with increased proliferation and decreased apoptosis. Elevated oleate (C18:1n-9) characterizes db/db islets and causes ER stress, inflammation, and apoptosis; Elovl6 deletion completely suppresses these. Ex vivo, Elovl6−/− islets exhibit reduced susceptibility to palmitate-induced inflammation, ER stress, and β-cell apoptosis, implicating oleate as the lipotoxic culprit downstream of ELOVL6.","method":"Elovl6 deletion in db/db mice; β-cell mass morphometry; islet isolation and ex vivo palmitate/oleate treatment; ER stress, inflammation, and apoptosis assays","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO in disease model plus mechanistic ex vivo islet experiments; multiple orthogonal readouts","pmids":["28461456"],"is_preprint":false},{"year":2018,"finding":"Loss of Elovl6 in Drosophila (Baldspot, the ELOVL6 ortholog) rescues retinal degeneration in a rhodopsin-G69D ER stress model by reducing IRE1 and PERK signaling and cell death. Dietary supplementation with stearate bypasses the need for Baldspot/ELOVL6 activity, placing ELOVL6-dependent C18 fatty acid production upstream of ER stress signaling.","method":"Drosophila genetic loss-of-function; retinitis pigmentosa ER stress model (Rh1G69D); IRE1 and PERK signaling measurement; dietary stearate supplementation rescue","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila ortholog KO with genetic epistasis and dietary rescue; single lab","pmids":["30081392"],"is_preprint":false},{"year":2018,"finding":"Elovl6 in keratinocytes regulates the balance of cis-vaccenic acid (CVA) levels in the epidermis. Elovl6-deficient mice accumulate higher CVA levels in epidermis; CVA accelerates tape stripping-triggered keratinocyte death and DAMP release (HMGB-1, IL-1α), inducing proinflammatory cytokines IL-1β and CXCL-1, causing severe mechanical damage-induced skin inflammation.","method":"Elovl6 knockout mice; tape stripping model; CVA fatty acid profiling; keratinocyte death and DAMP release assays; cytokine measurement","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with mechanistic cell-death and DAMP readout; single lab","pmids":["30518914"],"is_preprint":false},{"year":2021,"finding":"ELOVL6 levels are lower in bortezomib-resistant multiple myeloma (MM) cells. Restoration of ELOVL6 in BTZ-resistant MM cells resensitizes them to bortezomib through upregulation of ELOVL6-dependent ceramide species, which are prerequisite for BTZ-induced ER stress and cell death. Depletion of ELOVL6 in parental MM cells suppresses BTZ-induced ER stress and cytotoxicity.","method":"ELOVL6 knockdown and restoration in MM cell lines; lipidomics of BTZ-induced lipidome changes; xenograft plasmacytoma mouse model; cell death and ER stress assays","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function in cell lines plus in vivo xenograft validation; lipidomics identifies ceramide as mechanistic mediator","pmids":["33821992"],"is_preprint":false},{"year":2021,"finding":"ELOVL6 directly interacts with ACSL4 (a key regulator of ferroptosis) as confirmed by co-immunoprecipitation. ELOVL6 overexpression reverses apatinib-induced ferroptosis in colorectal cancer HCT116 cells, placing ELOVL6 upstream of ACSL4 in the ferroptosis pathway.","method":"Co-immunoprecipitation (co-IP); ELOVL6 overexpression in HCT116 cells; CCK-8 cell viability; iron/ROS measurement; Western blot of ferroptosis markers","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP without reciprocal validation; single lab, single method for protein interaction","pmids":["33603479"],"is_preprint":false},{"year":2021,"finding":"SREBP1 directly binds to SRE1 and SRE3 sites in the ELOVL6 promoter in goat mammary epithelial cells. Mutation of either SRE1 or SRE3 significantly reduced promoter activity; simultaneous mutation abolished SREBF1-stimulatory and linoleic acid-repressive effects on ELOVL6 transcription.","method":"Promoter deletion analysis; site-directed mutagenesis; luciferase reporter assay; ChIP assay in goat mammary epithelial cells (GMEC)","journal":"Journal of dairy science","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP plus mutagenesis of functional elements; single lab, single non-human tissue model","pmids":["33685712"],"is_preprint":false},{"year":2022,"finding":"ELOVL6 deficiency aggravates allergic airway inflammation via the ceramide-S1P pathway. Elovl6−/− asthmatic mice have elevated palmitic acid, ceramide, and sphingosine-1-phosphate in lung tissue, and enhanced lymphocyte egress from lymph nodes with upregulated type 2 and non-type 2 immune responses. Treatment with fumonisin B1 (ceramide synthase inhibitor) or DL-threo-dihydrosphingosine (sphingosine kinase inhibitor) ameliorates the aggravated inflammation, placing ELOVL6 upstream of ceramide-S1P biosynthesis in airway inflammation.","method":"Elovl6 knockout mice; OVA and HDM asthma models; lipidomic profiling; pharmacological inhibition of ceramide synthase and sphingosine kinase","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse in two asthma models plus pharmacological rescue experiments identifying ceramide-S1P pathway; multiple orthogonal methods","pmids":["36592705"],"is_preprint":false},{"year":2023,"finding":"ELOVL6 promotes inflammatory foam cell formation during demyelination, hampering remyelination. ELOVL6 is upregulated in myelin-phagocytosing phagocytes and MS lesions. Elovl6 depletion induces a repair-promoting phagocyte phenotype via S1P/PPARγ pathway activation, enhancing ABCA1-mediated lipid efflux and increasing neurotrophic factor production while reducing inflammatory mediators. In vivo, Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the cuprizone model.","method":"In vitro myelin-induced foam cell model; Elovl6 depletion; S1P/PPARγ signaling assays; ABCA1 efflux measurement; 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 / Strong — in vitro mechanistic pathway (S1P/PPARγ, ABCA1) plus two in vivo models (brain slices, cuprizone); multiple orthogonal methods","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 downregulate ELOVL6 by binding its 3'-UTR. miR-135b-5p and miR-135a-5p suppress glioblastoma cell proliferation and migration specifically by inhibiting ELOVL6 at the mRNA and protein levels.","method":"Dual-luciferase reporter assays with ELOVL6 3'-UTR constructs; miRNA overexpression in GBM cells; cell proliferation and migration assays","journal":"BBA advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay plus functional cell readout; single lab; establishes post-transcriptional ELOVL6 regulation in human cells","pmids":["37082255"],"is_preprint":false},{"year":2025,"finding":"ELOVL6 activity is required for production of phospholipids that KRAS-G12V exploits for membrane association. CRISPR-Cas9 genome-wide KO screens identified ELOVL6 as a selective modulator of KRAS-G12V protein expression. ELOVL6 targeting depletes specific phospholipid species, leading to function-targeted and trigger-targeted degradation of KRAS-G12V protein. A first-in-class small-molecule ELOVL6 inhibitor selectively clears KRAS-G12V from cancer cells.","method":"CRISPR-Cas9 genome-wide knockout screen; lipidomics; ELOVL6 inhibitor treatment; KRAS protein expression and degradation assays in cell lines","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide unbiased screen plus mechanistic lipidomics and pharmacological validation; multiple orthogonal methods; published in high-tier journal","pmids":["40954224"],"is_preprint":false},{"year":2025,"finding":"c-MYC directly upregulates ELOVL6 transcription during PDAC tumor progression. Genetic or chemical inhibition of ELOVL6 reduces cancer cell proliferation and migration by altering fatty acid composition, changing membrane rigidity, permeability, and pinocytosis, increasing Abraxane uptake and showing synergistic anti-tumor effects in vivo.","method":"PDAC mouse models; c-MYC ChIP/reporter for ELOVL6 regulation; ELOVL6 KD and inhibitor; fatty acid profiling; membrane biophysics; pinocytosis assays; in vivo tumor growth and Abraxane response","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct c-MYC regulation established plus multiple functional readouts in vitro and in vivo; confirmed in both genetic and pharmacological approaches","pmids":["39956817"],"is_preprint":false},{"year":2025,"finding":"ELOVL6 knockdown in FGFR3-mutant bladder cancer cells causes marked reduction in phosphatidylethanolamine, lowers mitochondrial complex I and II protein levels, and impairs mitochondrial oxidative phosphorylation (OXPHOS). This is accompanied by activation of ECM-integrin-FAK pathway as a compensatory response. ELOVL6 knockdown suppresses tumor progression in vivo.","method":"ELOVL6 knockdown in BC cell lines; lipidomics; RNA sequencing; mitochondrial OXPHOS assay; in vivo tumor growth assay","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lipidomics plus transcriptomics plus functional OXPHOS assay and in vivo validation; single lab","pmids":["40835210"],"is_preprint":false},{"year":2026,"finding":"Stearic acid (the direct product of ELOVL6 activity) promotes mitochondrial fusion by stabilizing mitofusin 1 (MFN1) protein in colorectal cancer cells. Elovl6 deficiency disrupts phospholipid biosynthesis, reduces stearic acid, destabilizes MFN1, impairs mitochondrial fusion, and promotes CRC progression.","method":"Elovl6 KO cells and mouse models; phospholipid profiling; MFN1 protein stability assay; mitochondrial morphology analysis; in vivo tumor growth","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link to MFN1 stabilization by stearic acid with in vitro and in vivo support; single lab, recent paper","pmids":["41686894"],"is_preprint":false},{"year":2020,"finding":"ChREBP binds to the Elovl6 promoter in vivo and drives histone H3 and H4 acetylation at the Elovl6 locus in high-fructose diet-induced fatty liver. myo-Inositol supplementation reduces ChREBP binding and histone acetylation at the Elovl6 promoter, suppressing Elovl6 expression.","method":"ChIP assay for ChREBP and SREBP-1 binding to Elovl6 promoter; histone acetylation ChIP; rat dietary model; qPCR","journal":"Nutrition research (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based evidence for in vivo promoter binding and epigenetic regulation; single lab, rat model","pmids":["33743322"],"is_preprint":false}],"current_model":"ELOVL6 is a microsomal fatty acid elongase that catalyzes the rate-limiting conversion of C16:0 (palmitate) to C18:0 (stearate) and C16:1 (palmitoleate) to C18:1 (vaccenate/oleate), is transcriptionally regulated by SREBP-1c (and ChREBP) via SRE elements in its promoter, and is post-transcriptionally regulated by multiple miRNAs; its enzymatic activity is allosterically enhanced by physical interaction with the downstream elongation enzyme KAR; alterations in ELOVL6-driven C16-to-C18 fatty acid balance modulate insulin signaling (via PKCε/IRS-2/Akt), NLRP3 inflammasome activation, ceramide-S1P biosynthesis, mitochondrial function (via phosphatidylethanolamine levels and MFN1 stabilization by stearate), KRAS-G12V membrane anchorage via phospholipids, and macrophage/phagocyte phenotype via S1P/PPARγ-ABCA1 signaling, positioning ELOVL6 as a central lipid-composition checkpoint in metabolic, inflammatory, and oncogenic processes."},"narrative":{"mechanistic_narrative":"ELOVL6 is the microsomal fatty acid elongase that catalyzes the rate-limiting conversion of palmitate (C16:0) to stearate (C18:0), and as the sole enzyme for this step it sets the cellular C16-to-C18 saturated fatty acid balance that propagates into downstream phospholipid, ceramide, and monounsaturated fatty acid pools [PMID:17906635, PMID:25281760]. Its enzymatic output is allosterically amplified by physical engagement with the downstream elongation enzyme KAR, which both induces an activity-enhancing conformational change in ELOVL6 and accelerates product release from the ELOVL6–KAR complex [PMID:25003994]. Transcription of ELOVL6 is driven directly by SREBP-1 through high-affinity SRE elements in its promoter [PMID:18226595, PMID:33685712] and by ChREBP, whose binding is coupled to histone H3/H4 acetylation at the locus under high-carbohydrate conditions [PMID:33743322]; c-MYC also transactivates ELOVL6 in pancreatic cancer [PMID:39956817], and the message is held in check post-transcriptionally by multiple miRNAs (miR-135a/b-5p, miR-125a/b-5p, miR-22-3p) acting on its 3'-UTR [PMID:37082255]. By tuning lipid composition, ELOVL6 functions as a checkpoint across metabolic, inflammatory, and oncogenic processes: it governs hepatic insulin signaling through PKCε/IRS-2/Akt [PMID:17906635], palmitate-driven NLRP3 inflammasome activation in NASH [PMID:22753171], saturated- and oleate-mediated lipotoxic ER stress and apoptosis in pancreatic β-cells [PMID:21266672, PMID:28461456], foam-cell formation and cholesterol efflux in macrophages and demyelinating lesions via the S1P/PPARγ–ABCA1 axis [PMID:21817094, PMID:37669365], ceramide–S1P-dependent airway inflammation [PMID:36592705], and mitochondrial integrity through phosphatidylethanolamine supply and stearate-dependent MFN1 stabilization [PMID:40835210, PMID:41686894]. In cancer, ELOVL6 supplies the phospholipid species required for KRAS-G12V membrane anchorage [PMID:40954224] and for membrane biophysical properties affecting drug uptake [PMID:39956817], making it a tractable small-molecule target [PMID:19505953, PMID:40954224].","teleology":[{"year":2007,"claim":"Established ELOVL6 as the elongase converting palmitate to stearate in vivo and linked its lipid output to hepatic insulin signaling, framing it as a metabolic checkpoint rather than a housekeeping enzyme.","evidence":"Elovl6 knockout mice on high-fat diet and ob/ob crosses, with hepatic IRS-2, PKCε, and Akt readouts","pmids":["17906635"],"confidence":"High","gaps":["Insulin-resistance protection was later not reproduced in an independent KO line","Direct molecular link between fatty acid composition and PKCε activity not resolved"]},{"year":2008,"claim":"Identified the transcriptional control point for ELOVL6, showing SREBP-1c binds defined SRE elements to drive its expression, placing the gene within lipogenic transcriptional programs.","evidence":"Luciferase reporters, EMSA, ChIP, and adenoviral SREBP-1 RNAi in mouse liver","pmids":["18226595"],"confidence":"High","gaps":["Did not address combinatorial regulation with other lipogenic transcription factors"]},{"year":2009,"claim":"Demonstrated ELOVL6 is selectively druggable and that inhibitor binding depends on palmitoyl-CoA, implying recognition of an acyl-enzyme intermediate and giving a chemical handle on catalysis.","evidence":"In vitro inhibition and [³H]Compound-A radioligand binding with selectivity profiling across ELOVL family","pmids":["19505953"],"confidence":"Medium","gaps":["No structural model of the inhibitor-bound enzyme","Single lab, single chemical series"]},{"year":2010,"claim":"Tested whether pharmacological ELOVL6 inhibition recapitulates the genetic insulin-sensitizing phenotype; chronic dosing altered hepatic fatty acid composition but did not improve insulin resistance.","evidence":"Oral ELOVL6 inhibitor in DIO and KKAy mice with hepatic lipid and insulin-resistance measurement","pmids":["20045404"],"confidence":"Medium","gaps":["Discordance with genetic KO insulin phenotype unexplained","Inhibitor exposure/target engagement in non-hepatic tissues not quantified"]},{"year":2011,"claim":"Extended ELOVL6 beyond metabolism into vascular and β-cell pathology, showing its lipid output determines macrophage foam-cell formation/cholesterol efflux and saturated-fat lipotoxicity.","evidence":"Bone marrow transplant of Elovl6−/− cells into LDL-R−/− mice with efflux assays; gain/loss-of-function in INS-1 β-cells","pmids":["21817094","21266672"],"confidence":"Medium","gaps":["Molecular link between elongated fatty acids and efflux transporter induction not fully defined","β-cell findings limited to a single cell line"]},{"year":2012,"claim":"Connected ELOVL6 lipid output to innate immune activation, showing palmitate-driven NLRP3 inflammasome activity underlies its role in steatohepatitis progression.","evidence":"Three Elovl6 loss- and gain-of-function mouse models on atherogenic diet with NLRP3 inflammasome readouts and human NASH samples","pmids":["22753171"],"confidence":"High","gaps":["Mechanism by which palmitate engages NLRP3 not delineated at molecular level"]},{"year":2013,"claim":"An independent KO line refined ELOVL6 substrate specificity (sole C16:0→C18:0 elongase, palmitoleate elongation not specific) but failed to reproduce protection from metabolic disease, exposing model-dependence of the insulin phenotype.","evidence":"Independent Elovl6 KO with high-fat and ob/ob crosses and mass-spectrometry lipidomics","pmids":["25281760"],"confidence":"High","gaps":["Source of discordance with the 2007 insulin phenotype unresolved","Genetic background contributions not isolated"]},{"year":2013,"claim":"Showed ELOVL6-dependent fatty acid balance maintains epithelial homeostasis, with its loss driving apoptosis, ROS, TGF-β1, and fibrosis in lung after injury.","evidence":"Elovl6 KO mouse with bleomycin challenge plus siRNA knockdown, ROS/apoptosis/TGF-β1 assays","pmids":["24113622"],"confidence":"High","gaps":["Specific lipid species driving the fibroproliferative response not pinpointed"]},{"year":2014,"claim":"Defined the biochemical basis for ELOVL6 activity regulation, revealing KAR enhances ELOVL6 both by conformational change and by enzymatic product release within a presumed complex.","evidence":"In vitro elongation assays with purified ELOVL6 and wild-type vs catalytically dead KAR mutants, with NADPH dependence","pmids":["25003994"],"confidence":"High","gaps":["Structure of the ELOVL6–KAR complex not determined","Stoichiometry and in vivo relevance of the interaction untested"]},{"year":2014,"claim":"Linked ELOVL6 to islet secretory function, with its ablation improving glucose-stimulated insulin secretion via ATP/ADP ratio and ATF-3 suppression.","evidence":"Elovl6 KO mice on high-fat/high-sucrose diet with islet GSIS, ATP/ADP, and ATF-3 measurement","pmids":["24938128"],"confidence":"Medium","gaps":["Causal lipid mediator linking elongation to ATP/ADP ratio not identified","Single lab"]},{"year":2015,"claim":"Showed ELOVL6-mediated C16→C18 conversion is required for full brown-fat thermogenic capacity through support of mitochondrial electron transport chain expression.","evidence":"Elovl6 KO mice with cold exposure, ETC component expression, and thermogenesis measurements","pmids":["26628376"],"confidence":"Medium","gaps":["Mechanism connecting fatty acid chain length to ETC component levels unresolved","Single lab"]},{"year":2016,"claim":"Established ELOVL6 as a regulator of vascular smooth muscle phenotype and chondrocyte/skeletal development, broadening its lipid-composition checkpoint role to differentiation programs.","evidence":"Elovl6−/− mice in wire-injury neointima model with VSMC ROS/AMPK/KLF4 epistasis; skeletal histology and Foxa2/HDAC analysis in chondrocytes","pmids":["27881420","27467521"],"confidence":"Medium","gaps":["How altered oleate/palmitate ratios initiate ROS/AMPK signaling not mechanistically closed","Chondrocyte findings from a single lab"]},{"year":2017,"claim":"Resolved the lipotoxic culprit downstream of ELOVL6 in diabetic islets, identifying elevated oleate as the driver of ER stress, inflammation, and β-cell apoptosis whose removal expands β-cell mass.","evidence":"Elovl6 deletion in db/db mice with β-cell morphometry and ex vivo islet palmitate/oleate challenge","pmids":["28461456"],"confidence":"High","gaps":["Receptor/sensor for oleate-induced ER stress not identified"]},{"year":2018,"claim":"Placed ELOVL6-dependent C18 fatty acid production upstream of UPR signaling and skin barrier inflammation, with stearate supplementation bypassing the requirement for the enzyme.","evidence":"Drosophila Baldspot loss-of-function with Rh1G69D ER-stress model and dietary stearate rescue; Elovl6 KO keratinocyte tape-stripping model with DAMP/cytokine readouts","pmids":["30081392","30518914"],"confidence":"Medium","gaps":["How stearate availability modulates IRE1/PERK signaling biochemically not defined","Findings from single labs in distinct systems"]},{"year":2020,"claim":"Added an epigenetic and second-transcription-factor layer, showing ChREBP binds the Elovl6 promoter and drives histone acetylation in fructose-induced fatty liver.","evidence":"ChIP for ChREBP/SREBP-1 binding and histone acetylation with myo-inositol intervention in a rat dietary model","pmids":["33743322"],"confidence":"Medium","gaps":["Relative contributions of ChREBP versus SREBP-1 not quantified","Rat model only"]},{"year":2021,"claim":"Linked ELOVL6 to therapy response in cancer, showing ELOVL6-dependent ceramide species are required for bortezomib-induced ER stress and that interaction with ACSL4 places it in the ferroptosis pathway.","evidence":"Knockdown/restoration in multiple myeloma cells with lipidomics and xenograft; co-IP and overexpression in colorectal HCT116 ferroptosis assays","pmids":["33821992","33603479"],"confidence":"Medium","gaps":["ACSL4 interaction rests on a single co-IP without reciprocal validation","Mechanism linking ELOVL6 elongation to ceramide synthesis not directly mapped"]},{"year":2022,"claim":"Defined ELOVL6 as an upstream brake on the ceramide–S1P axis in airway immunity, with its loss elevating ceramide/S1P and aggravating allergic inflammation reversible by pathway inhibitors.","evidence":"Elovl6 KO mice in OVA and HDM asthma models with lipidomics and ceramide synthase/sphingosine kinase inhibitor rescue","pmids":["36592705"],"confidence":"High","gaps":["How loss of C18 fatty acids shifts flux toward ceramide/S1P not biochemically detailed"]},{"year":2023,"claim":"Showed ELOVL6 drives a pro-inflammatory phagocyte phenotype during demyelination via the S1P/PPARγ–ABCA1 axis, and identified human miRNAs that post-transcriptionally repress it.","evidence":"Myelin-induced foam cell model, Elovl6 depletion with S1P/PPARγ and ABCA1 readouts, organotypic slices and cuprizone model; dual-luciferase 3'-UTR assays in glioblastoma cells","pmids":["37669365","37082255"],"confidence":"High","gaps":["Whether the same miRNAs regulate ELOVL6 in phagocytes not tested","Lipid species coupling ELOVL6 to S1P/PPARγ activation not specified"]},{"year":2025,"claim":"Revealed an oncogene-supporting role in which ELOVL6 supplies phospholipids required for KRAS-G12V membrane anchorage and membrane biophysics, and showed c-MYC drives its expression, validating it as a small-molecule target in cancer.","evidence":"Genome-wide CRISPR-Cas9 screen, lipidomics, and ELOVL6 inhibitor clearing KRAS-G12V; PDAC models with c-MYC ChIP/reporter, membrane biophysics, pinocytosis, and Abraxane response","pmids":["40954224","39956817"],"confidence":"High","gaps":["Identity of the specific KRAS-anchoring phospholipid species incompletely defined","Therapeutic window of ELOVL6 inhibition in vivo not established"]},{"year":2025,"claim":"Connected ELOVL6 to mitochondrial structure and function in cancer, showing knockdown depletes phosphatidylethanolamine and impairs OXPHOS with compensatory ECM-integrin-FAK signaling.","evidence":"ELOVL6 knockdown in FGFR3-mutant bladder cancer cells with lipidomics, RNA-seq, OXPHOS assays, and in vivo tumor growth","pmids":["40835210"],"confidence":"Medium","gaps":["Whether PE loss directly causes the complex I/II decline not isolated","Single lab"]},{"year":2026,"claim":"Provided a molecular mechanism for ELOVL6's effect on mitochondrial dynamics, showing its product stearate stabilizes MFN1 to promote mitochondrial fusion.","evidence":"Elovl6 KO cells and mouse models with phospholipid profiling, MFN1 stability and mitochondrial morphology assays, and in vivo tumor growth","pmids":["41686894"],"confidence":"Medium","gaps":["Biochemical mechanism by which stearate stabilizes MFN1 protein not defined","Single lab, recent finding"]},{"year":null,"claim":"A unifying biochemical and structural account of how ELOVL6-set C16/C18 ratios are transduced into the diverse downstream signaling outcomes (PKCε, NLRP3, ceramide-S1P, KRAS anchorage, MFN1) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of ELOVL6 or the ELOVL6–KAR complex","The specific lipid intermediates linking elongation to each downstream pathway are not consistently identified","Reconciliation of discordant metabolic phenotypes across independent KO lines is incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,7,9]}],"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":[0,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,19,24,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,20,21]}],"complexes":["ELOVL6-KAR elongase complex"],"partners":["KAR","ACSL4"],"other_free_text":[]}},"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. 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 that elongates fatty acids with 12, 14 and 16 carbons with higher activity toward C16:0 acyl-CoAs. Catalyzes the synthesis of unsaturated C16 long chain fatty acids and, to a lesser extent, C18:0 and those with low desaturation degree. May participate in the production of saturated and monounsaturated 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/Q9H5J4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELOVL6","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000170522","cell_line_id":"CID000319","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"SNRNP48","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000319","total_profiled":1310},"omim":[{"mim_id":"611546","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 6; ELOVL6","url":"https://www.omim.org/entry/611546"},{"mim_id":"610057","title":"TRANS-2,3-ENOYL-CoA REDUCTASE; TECR","url":"https://www.omim.org/entry/610057"},{"mim_id":"125853","title":"TYPE 2 DIABETES MELLITUS; T2D","url":"https://www.omim.org/entry/125853"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":31.1}],"url":"https://www.proteinatlas.org/search/ELOVL6"},"hgnc":{"alias_symbol":["FLJ23378","MGC5487","LCE"],"prev_symbol":[]},"alphafold":{"accession":"Q9H5J4","domains":[{"cath_id":"-","chopping":"2-190","consensus_level":"high","plddt":93.3124,"start":2,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5J4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5J4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5J4-F1-predicted_aligned_error_v6.png","plddt_mean":92.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELOVL6","jax_strain_url":"https://www.jax.org/strain/search?query=ELOVL6"},"sequence":{"accession":"Q9H5J4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H5J4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H5J4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5J4"}},"corpus_meta":[{"pmid":"17906635","id":"PMC_17906635","title":"Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance.","date":"2007","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17906635","citation_count":433,"is_preprint":false},{"pmid":"19169255","id":"PMC_19169255","title":"Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19169255","citation_count":363,"is_preprint":false},{"pmid":"22753171","id":"PMC_22753171","title":"Elovl6 promotes nonalcoholic steatohepatitis.","date":"2012","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22753171","citation_count":156,"is_preprint":false},{"pmid":"19259639","id":"PMC_19259639","title":"Elovl6: a new player in fatty acid metabolism and insulin sensitivity.","date":"2009","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/19259639","citation_count":145,"is_preprint":false},{"pmid":"24113622","id":"PMC_24113622","title":"Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice.","date":"2013","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24113622","citation_count":99,"is_preprint":false},{"pmid":"1397682","id":"PMC_1397682","title":"Isolation of cDNAs for LCE and HCE, two constituent proteases of the hatching enzyme of Oryzias latipes, and concurrent expression of their mRNAs during development.","date":"1992","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/1397682","citation_count":95,"is_preprint":false},{"pmid":"21266672","id":"PMC_21266672","title":"Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic β-cells by stearoyl-CoA desaturase and Elovl6.","date":"2011","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21266672","citation_count":95,"is_preprint":false},{"pmid":"18226595","id":"PMC_18226595","title":"Mouse Elovl-6 promoter is an SREBP target.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18226595","citation_count":92,"is_preprint":false},{"pmid":"21435436","id":"PMC_21435436","title":"Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups.","date":"2011","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21435436","citation_count":89,"is_preprint":false},{"pmid":"33603479","id":"PMC_33603479","title":"Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33603479","citation_count":69,"is_preprint":false},{"pmid":"25281760","id":"PMC_25281760","title":"Deletion of ELOVL6 blocks the synthesis of oleic acid but does not prevent the development of fatty liver or insulin resistance.","date":"2014","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/25281760","citation_count":69,"is_preprint":false},{"pmid":"26628376","id":"PMC_26628376","title":"Brown Adipose Tissue Thermogenic Capacity Is Regulated by Elovl6.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26628376","citation_count":67,"is_preprint":false},{"pmid":"28634035","id":"PMC_28634035","title":"Psoriasis-Associated Late Cornified Envelope (LCE) Proteins Have Antibacterial Activity.","date":"2017","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28634035","citation_count":64,"is_preprint":false},{"pmid":"2656665","id":"PMC_2656665","title":"Isolation and some properties of low choriolytic enzyme (LCE), a component of the hatching enzyme of the teleost, Oryzias latipes.","date":"1989","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2656665","citation_count":59,"is_preprint":false},{"pmid":"23341976","id":"PMC_23341976","title":"Polymorphism in the ELOVL6 gene is associated with a major QTL effect on fatty acid composition in pigs.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23341976","citation_count":54,"is_preprint":false},{"pmid":"29700319","id":"PMC_29700319","title":"Elovl6 is a negative clinical predictor for liver cancer and knockdown of Elovl6 reduces murine liver cancer progression.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29700319","citation_count":50,"is_preprint":false},{"pmid":"27881420","id":"PMC_27881420","title":"Elongation of Long-Chain Fatty Acid Family Member 6 (Elovl6)-Driven Fatty Acid Metabolism Regulates Vascular Smooth Muscle Cell Phenotype Through AMP-Activated Protein Kinase/Krüppel-Like Factor 4 (AMPK/KLF4) Signaling.","date":"2016","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/27881420","citation_count":50,"is_preprint":false},{"pmid":"22266797","id":"PMC_22266797","title":"Novel qualitative aspects of tissue fatty acids related to metabolic regulation: lessons from Elovl6 knockout.","date":"2012","source":"Progress in lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/22266797","citation_count":43,"is_preprint":false},{"pmid":"21817094","id":"PMC_21817094","title":"Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice.","date":"2011","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21817094","citation_count":37,"is_preprint":false},{"pmid":"31901374","id":"PMC_31901374","title":"Effect of ELOVL6 on the lipid metabolism of bovine adipocytes.","date":"2019","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31901374","citation_count":36,"is_preprint":false},{"pmid":"28461456","id":"PMC_28461456","title":"Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity.","date":"2017","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/28461456","citation_count":36,"is_preprint":false},{"pmid":"21208785","id":"PMC_21208785","title":"Variants in MHC, LCE and IL12B have epistatic effects on psoriasis risk in Chinese population.","date":"2010","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/21208785","citation_count":33,"is_preprint":false},{"pmid":"33479581","id":"PMC_33479581","title":"Role of fatty acid elongase Elovl6 in the regulation of energy metabolism and pathophysiological significance in diabetes.","date":"2020","source":"Diabetology international","url":"https://pubmed.ncbi.nlm.nih.gov/33479581","citation_count":33,"is_preprint":false},{"pmid":"25887840","id":"PMC_25887840","title":"Epigenetic regulation of the ELOVL6 gene is associated with a major QTL effect on fatty acid composition in pigs.","date":"2015","source":"Genetics, selection, evolution : GSE","url":"https://pubmed.ncbi.nlm.nih.gov/25887840","citation_count":33,"is_preprint":false},{"pmid":"30518914","id":"PMC_30518914","title":"Elovl6 regulates mechanical damage-induced keratinocyte death and skin inflammation.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30518914","citation_count":31,"is_preprint":false},{"pmid":"29510523","id":"PMC_29510523","title":"Liquid Crystal Elastomers-A Path to Biocompatible and Biodegradable 3D-LCE Scaffolds for Tissue Regeneration.","date":"2018","source":"Materials (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29510523","citation_count":30,"is_preprint":false},{"pmid":"26619823","id":"PMC_26619823","title":"Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26619823","citation_count":30,"is_preprint":false},{"pmid":"21701577","id":"PMC_21701577","title":"ELOVL6 genetic variation is related to insulin sensitivity: a new candidate gene in energy metabolism.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21701577","citation_count":27,"is_preprint":false},{"pmid":"33821992","id":"PMC_33821992","title":"The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma.","date":"2021","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/33821992","citation_count":25,"is_preprint":false},{"pmid":"30979053","id":"PMC_30979053","title":"Molecular Cloning, Characterization, and Nutritional Regulation of Elovl6 in Large Yellow Croaker (Larimichthys crocea).","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30979053","citation_count":25,"is_preprint":false},{"pmid":"24262945","id":"PMC_24262945","title":"The effect of LXRα, ChREBP and Elovl6 in liver and white adipose tissue on medium- and long-chain fatty acid diet-induced insulin resistance.","date":"2013","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/24262945","citation_count":24,"is_preprint":false},{"pmid":"37669365","id":"PMC_37669365","title":"Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37669365","citation_count":23,"is_preprint":false},{"pmid":"28445717","id":"PMC_28445717","title":"Hepatic ELOVL6 mRNA is regulated by the gga-miR-22-3p in egg-laying hen.","date":"2017","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/28445717","citation_count":22,"is_preprint":false},{"pmid":"32120850","id":"PMC_32120850","title":"Estrogen Abolishes the Repression Role of gga-miR-221-5p Targeting ELOVL6 and SQLE to Promote Lipid Synthesis in Chicken Liver.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32120850","citation_count":22,"is_preprint":false},{"pmid":"25003994","id":"PMC_25003994","title":"Two modes of regulation of the fatty acid elongase ELOVL6 by the 3-ketoacyl-CoA reductase KAR in the fatty acid elongation cycle.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25003994","citation_count":22,"is_preprint":false},{"pmid":"26556599","id":"PMC_26556599","title":"Late cornified envelope (LCE) proteins: distinct expression patterns of LCE2 and LCE3 members suggest nonredundant roles in human epidermis and other epithelia.","date":"2016","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/26556599","citation_count":21,"is_preprint":false},{"pmid":"30081392","id":"PMC_30081392","title":"Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30081392","citation_count":20,"is_preprint":false},{"pmid":"32325903","id":"PMC_32325903","title":"Quantitative Phosphoproteomic Analysis Reveals the Regulatory Networks of Elovl6 on Lipid and Glucose Metabolism in Zebrafish.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32325903","citation_count":20,"is_preprint":false},{"pmid":"29733968","id":"PMC_29733968","title":"Molecular characterization of elongase of very long-chain fatty acids 6 (elovl6) genes in Misgurnus anguillicaudatus and their potential roles in adaptation to cold temperature.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29733968","citation_count":20,"is_preprint":false},{"pmid":"36592705","id":"PMC_36592705","title":"ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice.","date":"2022","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36592705","citation_count":17,"is_preprint":false},{"pmid":"20045404","id":"PMC_20045404","title":"Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6.","date":"2010","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20045404","citation_count":17,"is_preprint":false},{"pmid":"32186869","id":"PMC_32186869","title":"Two Elongases, Elovl4 and Elovl6, Fulfill the Elongation Routes of the LC-PUFA Biosynthesis Pathway in the Orange Mud Crab (Scylla olivacea).","date":"2020","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32186869","citation_count":17,"is_preprint":false},{"pmid":"33685712","id":"PMC_33685712","title":"ELOVL6 promoter binding sites directly targeted by sterol regulatory element binding protein 1 in fatty acid synthesis of goat mammary epithelial cells.","date":"2021","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/33685712","citation_count":16,"is_preprint":false},{"pmid":"24938128","id":"PMC_24938128","title":"Ablation of Elovl6 protects pancreatic islets from high-fat diet-induced impairment of insulin secretion.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24938128","citation_count":15,"is_preprint":false},{"pmid":"39956817","id":"PMC_39956817","title":"Targeting ELOVL6 to disrupt c-MYC driven lipid metabolism in pancreatic cancer enhances chemosensitivity.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39956817","citation_count":12,"is_preprint":false},{"pmid":"33742447","id":"PMC_33742447","title":"Elongase of very long chain fatty acids 6 (ELOVL6) promotes lipid synthesis in buffalo mammary epithelial cells.","date":"2021","source":"Journal of animal physiology and animal nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/33742447","citation_count":12,"is_preprint":false},{"pmid":"32050615","id":"PMC_32050615","title":"Molecular Characterization, Nutritional and Insulin Regulation of Elovl6 in Rainbow Trout (Oncorhynchus mykiss).","date":"2020","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/32050615","citation_count":11,"is_preprint":false},{"pmid":"39080336","id":"PMC_39080336","title":"Identifying MSMO1, ELOVL6, AACS, and CERS2 related to lipid metabolism as biomarkers of Parkinson's disease.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39080336","citation_count":10,"is_preprint":false},{"pmid":"21511732","id":"PMC_21511732","title":"TALE homeodomain proteins regulate site-specific terminal differentiation, LCE genes and epidermal barrier.","date":"2011","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/21511732","citation_count":10,"is_preprint":false},{"pmid":"23903678","id":"PMC_23903678","title":"Genetic analysis of the ELOVL6 gene polymorphism associated with type 2 diabetes mellitus.","date":"2013","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/23903678","citation_count":10,"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":"27467521","id":"PMC_27467521","title":"Crucial Role of Elovl6 in Chondrocyte Growth and Differentiation during Growth Plate Development in Mice.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27467521","citation_count":9,"is_preprint":false},{"pmid":"23933272","id":"PMC_23933272","title":"A novel t(4;16)(q25;q23.1) associated with EGF and ELOVL6 deregulation in acute myeloid leukemia.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23933272","citation_count":9,"is_preprint":false},{"pmid":"37082255","id":"PMC_37082255","title":"Identification of key microRNAs regulating ELOVL6 and glioblastoma tumorigenesis.","date":"2023","source":"BBA advances","url":"https://pubmed.ncbi.nlm.nih.gov/37082255","citation_count":8,"is_preprint":false},{"pmid":"38426809","id":"PMC_38426809","title":"ELOVL6 promotes the progression of head and neck squamous cell carcinoma via activating WNT/β-catenin pathway.","date":"2024","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38426809","citation_count":7,"is_preprint":false},{"pmid":"31956234","id":"PMC_31956234","title":"FADS2 and ELOVL6 mutation frequencies in Japanese Crohn's disease patients.","date":"2019","source":"Drug discoveries & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31956234","citation_count":7,"is_preprint":false},{"pmid":"37520818","id":"PMC_37520818","title":"Cloning and expression characterization of elongation of very long-chain fatty acids protein 6 (elovl6) with dietary fatty acids, ambient salinity and starvation stress in Scylla paramamosain.","date":"2023","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37520818","citation_count":7,"is_preprint":false},{"pmid":"33743322","id":"PMC_33743322","title":"Dietary supplementation with myo-inositol reduces high-fructose diet-induced hepatic ChREBP binding and acetylation of histones H3 and H4 on the Elovl6 gene in rats.","date":"2020","source":"Nutrition research (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33743322","citation_count":7,"is_preprint":false},{"pmid":"29397434","id":"PMC_29397434","title":"Association between LCE gene polymorphisms and psoriasis vulgaris among Mongolians from Inner Mongolia.","date":"2018","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/29397434","citation_count":6,"is_preprint":false},{"pmid":"39675554","id":"PMC_39675554","title":"Emerging insights on the role of Elovl6 in human diseases: Therapeutic challenges and opportunities.","date":"2024","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39675554","citation_count":6,"is_preprint":false},{"pmid":"26329544","id":"PMC_26329544","title":"[SREBP-1c and Elovl6 as Targets for Obesity-related Disorders].","date":"2015","source":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","url":"https://pubmed.ncbi.nlm.nih.gov/26329544","citation_count":6,"is_preprint":false},{"pmid":"28225172","id":"PMC_28225172","title":"MiR-144 affects fatty acid composition by regulating ELOVL6 expression in duck hepatocytes.","date":"2017","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/28225172","citation_count":6,"is_preprint":false},{"pmid":"35491151","id":"PMC_35491151","title":"[Role of Fatty Acid Elongase Elovl6 in the Regulation of Fatty Acid Quality and Lifestyle-related Diseases].","date":"2022","source":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","url":"https://pubmed.ncbi.nlm.nih.gov/35491151","citation_count":5,"is_preprint":false},{"pmid":"38929334","id":"PMC_38929334","title":"m6A Methylation Mediates the Function of the circRNA-08436/miR-195/ELOVL6 Axis in Regards to Lipid Metabolism in Dairy Goat Mammary Glands.","date":"2024","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/38929334","citation_count":5,"is_preprint":false},{"pmid":"27030498","id":"PMC_27030498","title":"[Expression and clinical significance of ELOVL6 gene in high-grade serous ovarian carcinoma].","date":"2016","source":"Zhonghua fu chan ke za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/27030498","citation_count":4,"is_preprint":false},{"pmid":"38760797","id":"PMC_38760797","title":"Low expression of ELOVL6 may be involved in fat loss in white adipose tissue of cancer-associated cachexia.","date":"2024","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/38760797","citation_count":4,"is_preprint":false},{"pmid":"37875037","id":"PMC_37875037","title":"The ELOVL6 homolog in Penaeus vannamei plays a dual role in fatty acid metabolism and immune response.","date":"2023","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37875037","citation_count":4,"is_preprint":false},{"pmid":"40835210","id":"PMC_40835210","title":"Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells.","date":"2025","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/40835210","citation_count":3,"is_preprint":false},{"pmid":"40253742","id":"PMC_40253742","title":"Total saponins from Panax japonicus alleviate insulin resistance via exosomal miR204/Elovl6-mediated adipocyte-macrophage crosstalk.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40253742","citation_count":3,"is_preprint":false},{"pmid":"38806081","id":"PMC_38806081","title":"Silencing the fatty acid elongase gene elovl6 induces reprogramming of nutrient metabolism in male Oreochromis niloticus.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38806081","citation_count":3,"is_preprint":false},{"pmid":"39551296","id":"PMC_39551296","title":"Regulatory mechanism of Elovl6 in lipid metabolism, antioxidant capacity, and immune function in Scylla paramamosain revealed by Ap-1.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39551296","citation_count":3,"is_preprint":false},{"pmid":"19505953","id":"PMC_19505953","title":"Identification and characterization of a selective radioligand for ELOVL6.","date":"2009","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19505953","citation_count":2,"is_preprint":false},{"pmid":"38955031","id":"PMC_38955031","title":"Alleviation effects of dexmedetomidine on myocardial ischemia/reperfusion injury through fatty acid metabolism pathway via Elovl6.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38955031","citation_count":2,"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":"40913417","id":"PMC_40913417","title":"FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40913417","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 biology","url":"https://pubmed.ncbi.nlm.nih.gov/39996802","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":"41686894","id":"PMC_41686894","title":"Elovl6 inhibits colorectal cancer progression through stearic acid-mediated mitochondrial fusion and metabolic reprogramming.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/41686894","citation_count":0,"is_preprint":false},{"pmid":"40958209","id":"PMC_40958209","title":"Cholesterol Intake and Atorvastatin Modulate SCD1 and ELOVL6 in Rat Retroperitoneal Adipose Tissue.","date":"2025","source":"Fundamental & clinical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40958209","citation_count":0,"is_preprint":false},{"pmid":"41289344","id":"PMC_41289344","title":"Genetic variation and mRNA expression of the ELOVL6 and CRTC2 genes in Kalmyk cattle.","date":"2025","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41289344","citation_count":0,"is_preprint":false},{"pmid":"42246265","id":"PMC_42246265","title":"Computational Analysis of ELOVL6 Structure and Inhibition for Rational Drug Design.","date":"2026","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/42246265","citation_count":0,"is_preprint":false},{"pmid":"41768220","id":"PMC_41768220","title":"Regulatory Mechanisms of Sterol Regulatory Element-Binding Protein-Dependent Human ELOVL6 Expression in Response to Free Fatty Acids.","date":"2026","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41768220","citation_count":0,"is_preprint":false},{"pmid":"42067127","id":"PMC_42067127","title":"miR-302 protects the liver from glucolipotoxicity-induced lipid accumulation through activating AMPK and suppressing Elovl6 in HepG2 cells and also in mice.","date":"2026","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42067127","citation_count":0,"is_preprint":false},{"pmid":"41421092","id":"PMC_41421092","title":"Exploring phytochemical inhibitors of fatty acid elongase ELOVL6 for targeted treatment of chronic myeloid leukemia: A comprehensive network-based drug discovery approach.","date":"2025","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41421092","citation_count":0,"is_preprint":false},{"pmid":"41882829","id":"PMC_41882829","title":"Dietary supplementation of myo-inositol for preventing fatty liver disease by altering hepatic epigenetic modifications in the transcribed regions of Fasn and Elovl6.","date":"2026","source":"Biomedical research (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/41882829","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.11.622928","title":"ELOVL6 as a Therapeutic Target: Disrupting c-MYC-Driven Lipid Metabolism to Enhance Chemotherapy in Pancreatic Cancer","date":"2024-11-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.11.622928","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.01.25324944","title":"Impact of Intended Isocaloric Early vs. Late Time-Restricted Eating on Plasma Lipidome in Women with Overweight or Obesity: Secondary Analysis of the ChronoFast Trial","date":"2025-04-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.01.25324944","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.01.24311339","title":"Individualized Hybrid Electroconvulsive Therapy (i-HECT) Shows Rapid Anti-Depressant Effect and Improved Cognition in Young Patients with Depression","date":"2024-08-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.01.24311339","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.24.600346","title":"High-resolution chromosome-level genome provides molecular insights into adaptive evolution in crabs","date":"2024-06-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.24.600346","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46918,"output_tokens":7980,"usd":0.130227,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17576,"output_tokens":6326,"usd":0.123015,"stage2_stop_reason":"end_turn"},"total_usd":0.253242,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"ELOVL6 is the microsomal elongase that catalyzes the conversion of palmitate (C16:0) to stearate (C18:0). Elovl6-knockout mice become obese and develop hepatosteatosis on high-fat diet but are markedly protected from hyperinsulinemia and hyperglycemia. The mechanism involves restoration of hepatic insulin receptor substrate-2 (IRS-2) and suppression of hepatic protein kinase C epsilon (PKCε) activity, resulting in restoration of Akt phosphorylation.\",\n      \"method\": \"Elovl6 knockout mouse model; high-fat diet and ob/ob mouse crosses; 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 / Strong — genetic KO with defined molecular phenotype (PKCε suppression, IRS-2 restoration, Akt phosphorylation) replicated in two independent obese mouse models; foundational paper widely replicated\",\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 SREBP binding sites (proximal SRE-1 and distal SRE-2) were identified, with SRE-1 showing higher affinity. SREBP-1c binds the Elovl6 promoter in vivo, and adenoviral RNAi knockdown of SREBP-1 in mouse liver suppresses Elovl6 mRNA.\",\n      \"method\": \"Luciferase reporter assays, EMSA, chromatin immunoprecipitation (ChIP), adenoviral RNAi knockdown in mouse liver\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, EMSA, ChIP, in vivo knockdown) in a single study; later replicated in goat mammary cells (PMID 33685712)\",\n      \"pmids\": [\"18226595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A selective inhibitor (Compound A, an indoledione) was identified that potently inhibits human and mouse ELOVL6 with >100-fold selectivity over other ELOVL family members. A tritiated form ([³H]Compound-A) binds ELOVL6 in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH, suggesting it recognizes an acyl-enzyme intermediate.\",\n      \"method\": \"Biochemical inhibition assay; radioligand binding assay with [³H]Compound-A; selectivity profiling across ELOVL family members\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzyme assay with selective chemical probe and radioligand binding; single lab, single paper\",\n      \"pmids\": [\"19505953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A novel orally active ELOVL6 inhibitor (Compound B) was developed that effectively inhibits ELOVL6 activity in vivo in diet-induced obese and KKAy mice, significantly reducing hepatic fatty acid composition. However, no improvement in insulin resistance was observed in these chronic pharmacological studies.\",\n      \"method\": \"In vivo chronic dosing of selective ELOVL6 inhibitor in DIO and KKAy mice; hepatic fatty acid composition analysis; insulin resistance measurement\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological tool in two in vivo models; single lab; negative result for insulin resistance is explicitly noted\",\n      \"pmids\": [\"20045404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ELOVL6 in macrophages promotes foam cell formation and atherosclerosis. Elovl6-deficient macrophages accumulate less esterified cholesterol upon acetylated-LDL exposure, show increased cholesterol efflux and upregulated cholesterol efflux transporters, and bone marrow transplantation of Elovl6−/− cells into LDL-R−/− mice results in significantly smaller aortic atherosclerotic lesions.\",\n      \"method\": \"Bone marrow transplantation into irradiated LDL-R−/− mice; cholesterol efflux assay; fatty acid composition analysis of esterified cholesterol fraction in macrophages\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo bone marrow transplant plus ex vivo macrophage cholesterol efflux assays; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"21817094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ELOVL6 overexpression in pancreatic β-cells (INS-1) increases palmitate elongation to stearate and increases palmitate-induced ER stress and apoptosis, whereas ELOVL6 knockdown limits palmitate elongation and attenuates ER stress and apoptosis. This establishes ELOVL6 activity as a determinant of saturated fatty acid lipotoxicity in β-cells.\",\n      \"method\": \"Overexpression and RNAi knockdown in INS-1 cells; fatty acid profiling; ER stress and apoptosis assays\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in cell model with lipid and cell-death readouts; single lab\",\n      \"pmids\": [\"21266672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ELOVL6 is a critical modulator of nonalcoholic steatohepatitis (NASH). Using three independent mouse models (loss and gain of function), deletion of Elovl6 reduces atherogenic diet-induced hepatic inflammation, oxidative stress, and fibrosis. Mechanistically, deletion of Elovl6 reduces palmitate-induced activation of the NLRP3 inflammasome.\",\n      \"method\": \"Elovl6 knockout and adenoviral overexpression mouse models; NASH dietary challenge; NLRP3 inflammasome activation assays; human NASH liver samples for expression correlation\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent mouse models (KO plus gain-of-function) with mechanistic NLRP3 inflammasome readout; multiple orthogonal approaches\",\n      \"pmids\": [\"22753171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ELOVL6 is the only enzyme capable of elongating palmitate (C16:0) to stearate (C18:0); Elovl6−/− mice accumulate palmitic and palmitoleic acids and are severely depleted of stearic and oleic acids. Unexpectedly, palmitoleate (C16:1 n-7) elongation to vaccenate (C18:1 n-7) was not specific to ELOVL6. Deletion of ELOVL6 did not protect mice from obesity, fatty liver, hyperglycemia, or hyperinsulinemia on a high-fat diet or in ob/ob background (contradicting PMID 17906635 in some respects).\",\n      \"method\": \"Elovl6 knockout mouse generation; high-fat diet and ob/ob crosses; detailed hepatic fatty acid profiling by mass spectrometry\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — independent KO mouse line with comprehensive lipidomics; contradicts insulin-resistance protection finding from PMID 17906635\",\n      \"pmids\": [\"25281760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of Elovl6 in alveolar type II epithelial cells causes derangement of fatty acid profile, induces apoptosis, TGF-β1 expression, and reactive oxygen species generation; Elovl6-deficient mice exhibit severe fibroproliferative response to bleomycin, establishing a role for ELOVL6 in maintaining lung homeostasis.\",\n      \"method\": \"Elovl6 knockout mouse + bleomycin intratracheal instillation model; Elovl6 siRNA knockdown in cells; fatty acid profiling; apoptosis and ROS assays; TGF-β1 measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model combined with siRNA knockdown, multiple mechanistic readouts (apoptosis, ROS, TGF-β1); replicated across in vivo and in vitro systems\",\n      \"pmids\": [\"24113622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KAR (3-ketoacyl-CoA reductase), which catalyzes the second step of the FA elongation cycle, regulates ELOVL6 via two modes: (1) a KAR enzyme activity-independent mode in which KAR protein induces conformational changes in ELOVL6 (~3-fold activity enhancement), and (2) a KAR enzyme activity-dependent mode in which conversion of 3-ketoacyl-CoA to 3-hydroxyacyl-CoA facilitates product release from a presumed ELOVL6-KAR complex, further enhancing ELOVL6 activity (~10-fold with NADPH present).\",\n      \"method\": \"In vitro FA elongation assays using membrane fractions; purified ELOVL6 activity assay with wild-type and catalytically dead KAR mutants; NADPH dependence experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted enzymatic assay with active-site KAR mutant dissecting two mechanistic modes; single lab but rigorous biochemistry\",\n      \"pmids\": [\"25003994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Elovl6 ablation protects pancreatic islets from high-fat/high-sucrose diet-induced impairment: Elovl6−/− islets show increased glucose-stimulated insulin secretion (GSIS) associated with an increased ATP/ADP ratio and suppression of ATF-3 expression, indicating Elovl6 affects insulin secretory capacity per β-cell.\",\n      \"method\": \"Elovl6 knockout mouse; HFHS diet challenge; islet GSIS measurement; ATP/ADP ratio; ATF-3 expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined β-cell functional readouts; single lab, single paper\",\n      \"pmids\": [\"24938128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Elovl6 is necessary for brown adipose tissue (BAT) thermogenic capacity. Loss of Elovl6 does not alter canonical BAT markers but reduces expression of mitochondrial electron transport chain components and lowers BAT thermogenic capacity, converting C16 to C18 fatty acid species being required for full thermogenic function.\",\n      \"method\": \"Elovl6 knockout mice; cold exposure; mitochondrial ETC component expression; BAT thermogenesis measurement; thermoneutrality and aging experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple functional readouts (ETC expression, thermogenesis capacity); single lab\",\n      \"pmids\": [\"26628376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Elovl6 inhibition in vascular smooth muscle cells (VSMCs) induces phenotypic switching via ROS production and AMPK/KLF4 signaling. Reduced oleate and increased palmitate from Elovl6 deficiency lead to ROS production, AMPK activation, induction of p53/p21, reduced mTOR phosphorylation, and robust KLF4 induction. KLF4 knockdown attenuates AMPK-induced phenotypic switching, identifying KLF4 as a bona fide AMPK target. Elovl6-null mice show markedly inhibited neointima formation after wire injury.\",\n      \"method\": \"Elovl6−/− mice with wire injury model; siRNA knockdown in VSMCs; PDGF-BB stimulation; ROS measurement; AMPK, mTOR phosphorylation; KLF4 KD epistasis\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo neointima model plus in vitro epistasis (KLF4 KD) with multiple signaling readouts; multiple orthogonal methods\",\n      \"pmids\": [\"27881420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Elovl6 plays a crucial role in chondrocyte growth and differentiation during growth plate development. Elovl6-null mice have reduced proliferating chondrocyte layer, elongated hypertrophic zone, and decreased trabecular bone. Elovl6 ablation elevates Collagen10α1 expression, associated with increased Foxa2/a3 and Mef2c mRNA and elevated nuclear Foxa2 and cytoplasmic HDAC4/5/7 protein levels.\",\n      \"method\": \"Elovl6 knockout mice; skeletal histology; gene expression analysis; protein level measurement of Foxa2, HDAC4/5/7 in chondrocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with histological and molecular mechanistic readouts in chondrocytes; single lab\",\n      \"pmids\": [\"27467521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In db/db mice (T2D model), Elovl6 deletion markedly increases β-cell mass with increased proliferation and decreased apoptosis. Elevated oleate (C18:1n-9) characterizes db/db islets and causes ER stress, inflammation, and apoptosis; Elovl6 deletion completely suppresses these. Ex vivo, Elovl6−/− islets exhibit reduced susceptibility to palmitate-induced inflammation, ER stress, and β-cell apoptosis, implicating oleate as the lipotoxic culprit downstream of ELOVL6.\",\n      \"method\": \"Elovl6 deletion in db/db mice; β-cell mass morphometry; islet isolation and ex vivo palmitate/oleate treatment; ER stress, inflammation, and apoptosis assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO in disease model plus mechanistic ex vivo islet experiments; multiple orthogonal readouts\",\n      \"pmids\": [\"28461456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of Elovl6 in Drosophila (Baldspot, the ELOVL6 ortholog) rescues retinal degeneration in a rhodopsin-G69D ER stress model by reducing IRE1 and PERK signaling and cell death. Dietary supplementation with stearate bypasses the need for Baldspot/ELOVL6 activity, placing ELOVL6-dependent C18 fatty acid production upstream of ER stress signaling.\",\n      \"method\": \"Drosophila genetic loss-of-function; retinitis pigmentosa ER stress model (Rh1G69D); IRE1 and PERK signaling measurement; dietary stearate supplementation rescue\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila ortholog KO with genetic epistasis and dietary rescue; single lab\",\n      \"pmids\": [\"30081392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Elovl6 in keratinocytes regulates the balance of cis-vaccenic acid (CVA) levels in the epidermis. Elovl6-deficient mice accumulate higher CVA levels in epidermis; CVA accelerates tape stripping-triggered keratinocyte death and DAMP release (HMGB-1, IL-1α), inducing proinflammatory cytokines IL-1β and CXCL-1, causing severe mechanical damage-induced skin inflammation.\",\n      \"method\": \"Elovl6 knockout mice; tape stripping model; CVA fatty acid profiling; keratinocyte death and DAMP release assays; cytokine measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with mechanistic cell-death and DAMP readout; single lab\",\n      \"pmids\": [\"30518914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL6 levels are lower in bortezomib-resistant multiple myeloma (MM) cells. Restoration of ELOVL6 in BTZ-resistant MM cells resensitizes them to bortezomib through upregulation of ELOVL6-dependent ceramide species, which are prerequisite for BTZ-induced ER stress and cell death. Depletion of ELOVL6 in parental MM cells suppresses BTZ-induced ER stress and cytotoxicity.\",\n      \"method\": \"ELOVL6 knockdown and restoration in MM cell lines; lipidomics of BTZ-induced lipidome changes; xenograft plasmacytoma mouse model; cell death and ER stress assays\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function in cell lines plus in vivo xenograft validation; lipidomics identifies ceramide as mechanistic mediator\",\n      \"pmids\": [\"33821992\"],\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 reverses apatinib-induced ferroptosis in colorectal cancer HCT116 cells, placing ELOVL6 upstream of ACSL4 in the ferroptosis pathway.\",\n      \"method\": \"Co-immunoprecipitation (co-IP); ELOVL6 overexpression in HCT116 cells; CCK-8 cell viability; iron/ROS measurement; Western blot of ferroptosis markers\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP without reciprocal validation; single lab, single method for protein interaction\",\n      \"pmids\": [\"33603479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SREBP1 directly binds to SRE1 and SRE3 sites in the ELOVL6 promoter in goat mammary epithelial cells. Mutation of either SRE1 or SRE3 significantly reduced promoter activity; simultaneous mutation abolished SREBF1-stimulatory and linoleic acid-repressive effects on ELOVL6 transcription.\",\n      \"method\": \"Promoter deletion analysis; site-directed mutagenesis; luciferase reporter assay; ChIP assay in goat mammary epithelial cells (GMEC)\",\n      \"journal\": \"Journal of dairy science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP plus mutagenesis of functional elements; single lab, single non-human tissue model\",\n      \"pmids\": [\"33685712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELOVL6 deficiency aggravates allergic airway inflammation via the ceramide-S1P pathway. Elovl6−/− asthmatic mice have elevated palmitic acid, ceramide, and sphingosine-1-phosphate in lung tissue, and enhanced lymphocyte egress from lymph nodes with upregulated type 2 and non-type 2 immune responses. Treatment with fumonisin B1 (ceramide synthase inhibitor) or DL-threo-dihydrosphingosine (sphingosine kinase inhibitor) ameliorates the aggravated inflammation, placing ELOVL6 upstream of ceramide-S1P biosynthesis in airway inflammation.\",\n      \"method\": \"Elovl6 knockout mice; OVA and HDM asthma models; lipidomic profiling; pharmacological inhibition of ceramide synthase and sphingosine kinase\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse in two asthma models plus pharmacological rescue experiments identifying ceramide-S1P pathway; multiple orthogonal methods\",\n      \"pmids\": [\"36592705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELOVL6 promotes inflammatory foam cell formation during demyelination, hampering remyelination. ELOVL6 is upregulated in myelin-phagocytosing phagocytes and MS lesions. Elovl6 depletion induces a repair-promoting phagocyte phenotype via S1P/PPARγ pathway activation, enhancing ABCA1-mediated lipid efflux and increasing neurotrophic factor production while reducing inflammatory mediators. In vivo, Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the cuprizone model.\",\n      \"method\": \"In vitro myelin-induced foam cell model; Elovl6 depletion; S1P/PPARγ signaling assays; ABCA1 efflux measurement; 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 / Strong — in vitro mechanistic pathway (S1P/PPARγ, ABCA1) plus two in vivo models (brain slices, cuprizone); multiple orthogonal methods\",\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 downregulate ELOVL6 by binding its 3'-UTR. miR-135b-5p and miR-135a-5p suppress glioblastoma cell proliferation and migration specifically by inhibiting ELOVL6 at the mRNA and protein levels.\",\n      \"method\": \"Dual-luciferase reporter assays with ELOVL6 3'-UTR constructs; miRNA overexpression in GBM cells; cell proliferation and migration assays\",\n      \"journal\": \"BBA advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay plus functional cell readout; single lab; establishes post-transcriptional ELOVL6 regulation in human cells\",\n      \"pmids\": [\"37082255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL6 activity is required for production of phospholipids that KRAS-G12V exploits for membrane association. CRISPR-Cas9 genome-wide KO screens identified ELOVL6 as a selective modulator of KRAS-G12V protein expression. ELOVL6 targeting depletes specific phospholipid species, leading to function-targeted and trigger-targeted degradation of KRAS-G12V protein. A first-in-class small-molecule ELOVL6 inhibitor selectively clears KRAS-G12V from cancer cells.\",\n      \"method\": \"CRISPR-Cas9 genome-wide knockout screen; lipidomics; ELOVL6 inhibitor treatment; KRAS protein expression and degradation assays in cell lines\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide unbiased screen plus mechanistic lipidomics and pharmacological validation; multiple orthogonal methods; published in high-tier journal\",\n      \"pmids\": [\"40954224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"c-MYC directly upregulates ELOVL6 transcription during PDAC tumor progression. Genetic or chemical inhibition of ELOVL6 reduces cancer cell proliferation and migration by altering fatty acid composition, changing membrane rigidity, permeability, and pinocytosis, increasing Abraxane uptake and showing synergistic anti-tumor effects in vivo.\",\n      \"method\": \"PDAC mouse models; c-MYC ChIP/reporter for ELOVL6 regulation; ELOVL6 KD and inhibitor; fatty acid profiling; membrane biophysics; pinocytosis assays; in vivo tumor growth and Abraxane response\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct c-MYC regulation established plus multiple functional readouts in vitro and in vivo; confirmed in both genetic and pharmacological approaches\",\n      \"pmids\": [\"39956817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL6 knockdown in FGFR3-mutant bladder cancer cells causes marked reduction in phosphatidylethanolamine, lowers mitochondrial complex I and II protein levels, and impairs mitochondrial oxidative phosphorylation (OXPHOS). This is accompanied by activation of ECM-integrin-FAK pathway as a compensatory response. ELOVL6 knockdown suppresses tumor progression in vivo.\",\n      \"method\": \"ELOVL6 knockdown in BC cell lines; lipidomics; RNA sequencing; mitochondrial OXPHOS assay; in vivo tumor growth assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipidomics plus transcriptomics plus functional OXPHOS assay and in vivo validation; single lab\",\n      \"pmids\": [\"40835210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Stearic acid (the direct product of ELOVL6 activity) promotes mitochondrial fusion by stabilizing mitofusin 1 (MFN1) protein in colorectal cancer cells. Elovl6 deficiency disrupts phospholipid biosynthesis, reduces stearic acid, destabilizes MFN1, impairs mitochondrial fusion, and promotes CRC progression.\",\n      \"method\": \"Elovl6 KO cells and mouse models; phospholipid profiling; MFN1 protein stability assay; mitochondrial morphology analysis; in vivo tumor growth\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link to MFN1 stabilization by stearic acid with in vitro and in vivo support; single lab, recent paper\",\n      \"pmids\": [\"41686894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ChREBP binds to the Elovl6 promoter in vivo and drives histone H3 and H4 acetylation at the Elovl6 locus in high-fructose diet-induced fatty liver. myo-Inositol supplementation reduces ChREBP binding and histone acetylation at the Elovl6 promoter, suppressing Elovl6 expression.\",\n      \"method\": \"ChIP assay for ChREBP and SREBP-1 binding to Elovl6 promoter; histone acetylation ChIP; rat dietary model; qPCR\",\n      \"journal\": \"Nutrition research (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based evidence for in vivo promoter binding and epigenetic regulation; single lab, rat model\",\n      \"pmids\": [\"33743322\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELOVL6 is a microsomal fatty acid elongase that catalyzes the rate-limiting conversion of C16:0 (palmitate) to C18:0 (stearate) and C16:1 (palmitoleate) to C18:1 (vaccenate/oleate), is transcriptionally regulated by SREBP-1c (and ChREBP) via SRE elements in its promoter, and is post-transcriptionally regulated by multiple miRNAs; its enzymatic activity is allosterically enhanced by physical interaction with the downstream elongation enzyme KAR; alterations in ELOVL6-driven C16-to-C18 fatty acid balance modulate insulin signaling (via PKCε/IRS-2/Akt), NLRP3 inflammasome activation, ceramide-S1P biosynthesis, mitochondrial function (via phosphatidylethanolamine levels and MFN1 stabilization by stearate), KRAS-G12V membrane anchorage via phospholipids, and macrophage/phagocyte phenotype via S1P/PPARγ-ABCA1 signaling, positioning ELOVL6 as a central lipid-composition checkpoint in metabolic, inflammatory, and oncogenic processes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELOVL6 is the microsomal fatty acid elongase that catalyzes the rate-limiting conversion of palmitate (C16:0) to stearate (C18:0), and as the sole enzyme for this step it sets the cellular C16-to-C18 saturated fatty acid balance that propagates into downstream phospholipid, ceramide, and monounsaturated fatty acid pools [#0, #7]. Its enzymatic output is allosterically amplified by physical engagement with the downstream elongation enzyme KAR, which both induces an activity-enhancing conformational change in ELOVL6 and accelerates product release from the ELOVL6–KAR complex [#9]. Transcription of ELOVL6 is driven directly by SREBP-1 through high-affinity SRE elements in its promoter [#1, #19] and by ChREBP, whose binding is coupled to histone H3/H4 acetylation at the locus under high-carbohydrate conditions [#27]; c-MYC also transactivates ELOVL6 in pancreatic cancer [#24], and the message is held in check post-transcriptionally by multiple miRNAs (miR-135a/b-5p, miR-125a/b-5p, miR-22-3p) acting on its 3'-UTR [#22]. By tuning lipid composition, ELOVL6 functions as a checkpoint across metabolic, inflammatory, and oncogenic processes: it governs hepatic insulin signaling through PKCε/IRS-2/Akt [#0], palmitate-driven NLRP3 inflammasome activation in NASH [#6], saturated- and oleate-mediated lipotoxic ER stress and apoptosis in pancreatic β-cells [#5, #14], foam-cell formation and cholesterol efflux in macrophages and demyelinating lesions via the S1P/PPARγ–ABCA1 axis [#4, #21], ceramide–S1P-dependent airway inflammation [#20], and mitochondrial integrity through phosphatidylethanolamine supply and stearate-dependent MFN1 stabilization [#25, #26]. In cancer, ELOVL6 supplies the phospholipid species required for KRAS-G12V membrane anchorage [#23] and for membrane biophysical properties affecting drug uptake [#24], making it a tractable small-molecule target [#2, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established ELOVL6 as the elongase converting palmitate to stearate in vivo and linked its lipid output to hepatic insulin signaling, framing it as a metabolic checkpoint rather than a housekeeping enzyme.\",\n      \"evidence\": \"Elovl6 knockout mice on high-fat diet and ob/ob crosses, with hepatic IRS-2, PKCε, and Akt readouts\",\n      \"pmids\": [\"17906635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Insulin-resistance protection was later not reproduced in an independent KO line\", \"Direct molecular link between fatty acid composition and PKCε activity not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the transcriptional control point for ELOVL6, showing SREBP-1c binds defined SRE elements to drive its expression, placing the gene within lipogenic transcriptional programs.\",\n      \"evidence\": \"Luciferase reporters, EMSA, ChIP, and adenoviral SREBP-1 RNAi in mouse liver\",\n      \"pmids\": [\"18226595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address combinatorial regulation with other lipogenic transcription factors\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated ELOVL6 is selectively druggable and that inhibitor binding depends on palmitoyl-CoA, implying recognition of an acyl-enzyme intermediate and giving a chemical handle on catalysis.\",\n      \"evidence\": \"In vitro inhibition and [³H]Compound-A radioligand binding with selectivity profiling across ELOVL family\",\n      \"pmids\": [\"19505953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the inhibitor-bound enzyme\", \"Single lab, single chemical series\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tested whether pharmacological ELOVL6 inhibition recapitulates the genetic insulin-sensitizing phenotype; chronic dosing altered hepatic fatty acid composition but did not improve insulin resistance.\",\n      \"evidence\": \"Oral ELOVL6 inhibitor in DIO and KKAy mice with hepatic lipid and insulin-resistance measurement\",\n      \"pmids\": [\"20045404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discordance with genetic KO insulin phenotype unexplained\", \"Inhibitor exposure/target engagement in non-hepatic tissues not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended ELOVL6 beyond metabolism into vascular and β-cell pathology, showing its lipid output determines macrophage foam-cell formation/cholesterol efflux and saturated-fat lipotoxicity.\",\n      \"evidence\": \"Bone marrow transplant of Elovl6−/− cells into LDL-R−/− mice with efflux assays; gain/loss-of-function in INS-1 β-cells\",\n      \"pmids\": [\"21817094\", \"21266672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between elongated fatty acids and efflux transporter induction not fully defined\", \"β-cell findings limited to a single cell line\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected ELOVL6 lipid output to innate immune activation, showing palmitate-driven NLRP3 inflammasome activity underlies its role in steatohepatitis progression.\",\n      \"evidence\": \"Three Elovl6 loss- and gain-of-function mouse models on atherogenic diet with NLRP3 inflammasome readouts and human NASH samples\",\n      \"pmids\": [\"22753171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which palmitate engages NLRP3 not delineated at molecular level\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"An independent KO line refined ELOVL6 substrate specificity (sole C16:0→C18:0 elongase, palmitoleate elongation not specific) but failed to reproduce protection from metabolic disease, exposing model-dependence of the insulin phenotype.\",\n      \"evidence\": \"Independent Elovl6 KO with high-fat and ob/ob crosses and mass-spectrometry lipidomics\",\n      \"pmids\": [\"25281760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of discordance with the 2007 insulin phenotype unresolved\", \"Genetic background contributions not isolated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed ELOVL6-dependent fatty acid balance maintains epithelial homeostasis, with its loss driving apoptosis, ROS, TGF-β1, and fibrosis in lung after injury.\",\n      \"evidence\": \"Elovl6 KO mouse with bleomycin challenge plus siRNA knockdown, ROS/apoptosis/TGF-β1 assays\",\n      \"pmids\": [\"24113622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lipid species driving the fibroproliferative response not pinpointed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the biochemical basis for ELOVL6 activity regulation, revealing KAR enhances ELOVL6 both by conformational change and by enzymatic product release within a presumed complex.\",\n      \"evidence\": \"In vitro elongation assays with purified ELOVL6 and wild-type vs catalytically dead KAR mutants, with NADPH dependence\",\n      \"pmids\": [\"25003994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the ELOVL6–KAR complex not determined\", \"Stoichiometry and in vivo relevance of the interaction untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked ELOVL6 to islet secretory function, with its ablation improving glucose-stimulated insulin secretion via ATP/ADP ratio and ATF-3 suppression.\",\n      \"evidence\": \"Elovl6 KO mice on high-fat/high-sucrose diet with islet GSIS, ATP/ADP, and ATF-3 measurement\",\n      \"pmids\": [\"24938128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal lipid mediator linking elongation to ATP/ADP ratio not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed ELOVL6-mediated C16→C18 conversion is required for full brown-fat thermogenic capacity through support of mitochondrial electron transport chain expression.\",\n      \"evidence\": \"Elovl6 KO mice with cold exposure, ETC component expression, and thermogenesis measurements\",\n      \"pmids\": [\"26628376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting fatty acid chain length to ETC component levels unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established ELOVL6 as a regulator of vascular smooth muscle phenotype and chondrocyte/skeletal development, broadening its lipid-composition checkpoint role to differentiation programs.\",\n      \"evidence\": \"Elovl6−/− mice in wire-injury neointima model with VSMC ROS/AMPK/KLF4 epistasis; skeletal histology and Foxa2/HDAC analysis in chondrocytes\",\n      \"pmids\": [\"27881420\", \"27467521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How altered oleate/palmitate ratios initiate ROS/AMPK signaling not mechanistically closed\", \"Chondrocyte findings from a single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the lipotoxic culprit downstream of ELOVL6 in diabetic islets, identifying elevated oleate as the driver of ER stress, inflammation, and β-cell apoptosis whose removal expands β-cell mass.\",\n      \"evidence\": \"Elovl6 deletion in db/db mice with β-cell morphometry and ex vivo islet palmitate/oleate challenge\",\n      \"pmids\": [\"28461456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/sensor for oleate-induced ER stress not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed ELOVL6-dependent C18 fatty acid production upstream of UPR signaling and skin barrier inflammation, with stearate supplementation bypassing the requirement for the enzyme.\",\n      \"evidence\": \"Drosophila Baldspot loss-of-function with Rh1G69D ER-stress model and dietary stearate rescue; Elovl6 KO keratinocyte tape-stripping model with DAMP/cytokine readouts\",\n      \"pmids\": [\"30081392\", \"30518914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How stearate availability modulates IRE1/PERK signaling biochemically not defined\", \"Findings from single labs in distinct systems\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added an epigenetic and second-transcription-factor layer, showing ChREBP binds the Elovl6 promoter and drives histone acetylation in fructose-induced fatty liver.\",\n      \"evidence\": \"ChIP for ChREBP/SREBP-1 binding and histone acetylation with myo-inositol intervention in a rat dietary model\",\n      \"pmids\": [\"33743322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of ChREBP versus SREBP-1 not quantified\", \"Rat model only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ELOVL6 to therapy response in cancer, showing ELOVL6-dependent ceramide species are required for bortezomib-induced ER stress and that interaction with ACSL4 places it in the ferroptosis pathway.\",\n      \"evidence\": \"Knockdown/restoration in multiple myeloma cells with lipidomics and xenograft; co-IP and overexpression in colorectal HCT116 ferroptosis assays\",\n      \"pmids\": [\"33821992\", \"33603479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ACSL4 interaction rests on a single co-IP without reciprocal validation\", \"Mechanism linking ELOVL6 elongation to ceramide synthesis not directly mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined ELOVL6 as an upstream brake on the ceramide–S1P axis in airway immunity, with its loss elevating ceramide/S1P and aggravating allergic inflammation reversible by pathway inhibitors.\",\n      \"evidence\": \"Elovl6 KO mice in OVA and HDM asthma models with lipidomics and ceramide synthase/sphingosine kinase inhibitor rescue\",\n      \"pmids\": [\"36592705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of C18 fatty acids shifts flux toward ceramide/S1P not biochemically detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ELOVL6 drives a pro-inflammatory phagocyte phenotype during demyelination via the S1P/PPARγ–ABCA1 axis, and identified human miRNAs that post-transcriptionally repress it.\",\n      \"evidence\": \"Myelin-induced foam cell model, Elovl6 depletion with S1P/PPARγ and ABCA1 readouts, organotypic slices and cuprizone model; dual-luciferase 3'-UTR assays in glioblastoma cells\",\n      \"pmids\": [\"37669365\", \"37082255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same miRNAs regulate ELOVL6 in phagocytes not tested\", \"Lipid species coupling ELOVL6 to S1P/PPARγ activation not specified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an oncogene-supporting role in which ELOVL6 supplies phospholipids required for KRAS-G12V membrane anchorage and membrane biophysics, and showed c-MYC drives its expression, validating it as a small-molecule target in cancer.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen, lipidomics, and ELOVL6 inhibitor clearing KRAS-G12V; PDAC models with c-MYC ChIP/reporter, membrane biophysics, pinocytosis, and Abraxane response\",\n      \"pmids\": [\"40954224\", \"39956817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific KRAS-anchoring phospholipid species incompletely defined\", \"Therapeutic window of ELOVL6 inhibition in vivo not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ELOVL6 to mitochondrial structure and function in cancer, showing knockdown depletes phosphatidylethanolamine and impairs OXPHOS with compensatory ECM-integrin-FAK signaling.\",\n      \"evidence\": \"ELOVL6 knockdown in FGFR3-mutant bladder cancer cells with lipidomics, RNA-seq, OXPHOS assays, and in vivo tumor growth\",\n      \"pmids\": [\"40835210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PE loss directly causes the complex I/II decline not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a molecular mechanism for ELOVL6's effect on mitochondrial dynamics, showing its product stearate stabilizes MFN1 to promote mitochondrial fusion.\",\n      \"evidence\": \"Elovl6 KO cells and mouse models with phospholipid profiling, MFN1 stability and mitochondrial morphology assays, and in vivo tumor growth\",\n      \"pmids\": [\"41686894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical mechanism by which stearate stabilizes MFN1 protein not defined\", \"Single lab, recent finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying biochemical and structural account of how ELOVL6-set C16/C18 ratios are transduced into the diverse downstream signaling outcomes (PKCε, NLRP3, ceramide-S1P, KRAS anchorage, MFN1) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of ELOVL6 or the ELOVL6–KAR complex\", \"The specific lipid intermediates linking elongation to each downstream pathway are not consistently identified\", \"Reconciliation of discordant metabolic phenotypes across independent KO lines is incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 7, 9]},\n      {\"term_id\": \"GO:0016747\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 19, 24, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 20, 21]}\n    ],\n    \"complexes\": [\"ELOVL6-KAR elongase complex\"],\n    \"partners\": [\"KAR\", \"ACSL4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}