{"gene":"ALOX15","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2023,"finding":"ALOX15 metabolite 15-HpETE promotes binding of PGC1α to the ubiquitin ligase RNF34, leading to ubiquitin-dependent degradation of PGC1α, attenuated mitochondrial biogenesis, and cardiomyocyte ferroptosis during myocardial ischemia-reperfusion injury.","method":"Loss/gain-of-function mouse models, metabolomics, co-immunoprecipitation, myocardial-specific knockout, pharmacologic inhibition (ML351)","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal mechanistic experiments with KO mice, metabolomics, co-IP, and pharmacologic rescue in a defined disease model","pmids":["36987924"],"is_preprint":false},{"year":2022,"finding":"ALOX15 is the primary mediator of ischemia-provoked PUFA-phospholipid peroxidation (specifically oxidized PUFAs in phosphatidylethanolamines) in cardiomyocytes, acting as a 'burning point' that initiates ferroptotic signals during reperfusion.","method":"Multi-omics, chemogenetic approaches, animal and in vitro models","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 — multi-omics with chemogenetic confirmation, orthogonal validation","pmids":["35970840"],"is_preprint":false},{"year":2000,"finding":"15-LOX-1 (ALOX15) is the main enzyme for metabolizing linoleic acid to 13-S-HODE in colon cells; NSAIDs increase 15-LOX-1 protein expression and enzymatic activity, and 13-S-HODE is the proximate inducer of apoptosis — inhibiting 15-LOX-1 blocks NSAID-induced apoptosis, which is restored by exogenous 13-S-HODE.","method":"Enzymatic activity assay, protein expression (Western blot), pharmacologic inhibition (caffeic acid), rescue with exogenous 13-S-HODE in colorectal cancer cell lines","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 1-2 — enzymatic activity confirmed, loss-of-function with inhibitor, rescue with product, replicated in two cell lines","pmids":["10904086"],"is_preprint":false},{"year":2004,"finding":"Alox15 (12/15-lipoxygenase) acts as a negative regulator of peak bone mineral density in mice; pharmacologic inhibitors of Alox15 improve bone density and strength in rodent osteoporosis models.","method":"Genetic crossbreeding with Alox15 knockout mice, pharmacologic inhibition, bone density/strength measurement","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — KO mouse crossbreeding plus pharmacologic confirmation, replicated in two rodent models","pmids":["14716014"],"is_preprint":false},{"year":2016,"finding":"The reaction specificity of mammalian ALOX15 evolved during late primate evolution: lower primates express 12-lipoxygenating ALOX15 orthologs, while higher primates (including humans) express 15-lipoxygenating enzymes; this switch optimizes lipoxin synthase activity, with 15-lipoxygenating variants having >5-fold higher lipoxin synthase activity. QM/MM calculations show lower energy barriers for C13-hydrogen abstraction (15-lipoxygenation) in rabbit ALOX15.","method":"Cloning and functional characterization of multiple ALOX15 orthologs, in vitro enzymatic assays, site-directed mutagenesis, molecular dynamics simulations, QM/MM calculations","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution, mutagenesis, and QM/MM calculations across multiple species orthologs","pmids":["27412860"],"is_preprint":false},{"year":2015,"finding":"Mutagenesis of triad determinants (Leu353, Ile593) in rat Alox15 alters positional specificity for both free fatty acids and complex ester lipids; rat Alox15 and its 15-lipoxygenating Leu353Phe mutant can oxygenate ester lipids of biomembranes and HDL.","method":"Recombinant protein expression, multiple directed mutagenesis, in vitro enzymatic assays with free and esterified substrates","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with mutagenesis of key catalytic determinants","pmids":["25731857"],"is_preprint":false},{"year":2017,"finding":"Human ALOX15, chimpanzee, and orangutan orthologs exhibit pronounced dual positional specificity with DHA, forming similar amounts of 14- and 17-HpDHA; ALOX15 orthologs preferentially oxygenate DHA and EPA over arachidonic acid when supplied simultaneously.","method":"Recombinant expression of ALOX15 orthologs from eight mammalian species, in vitro enzymatic assays with multiple PUFA substrates","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1 — recombinant enzyme characterization across multiple orthologs with systematic substrate panels","pmids":["28400162"],"is_preprint":false},{"year":2020,"finding":"15-LOX-1 peroxidation of linoleic acid in phosphatidylinositol-3-phosphates (PI3P_LA) generates PI3P_13-HODE, which decreases PI3P binding to SNX17 and LRP5, inhibits LRP5 recycling from endosomes to the plasma membrane, increases LRP5 lysosomal degradation, and suppresses Wnt/β-catenin signaling to inhibit colorectal carcinogenesis.","method":"15-LOX-1 transgenic mouse intestinal expression, APC-mutant mouse model, in vitro mechanistic studies with PI3P-lipid binding assays, endosome tracking","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — transgenic mouse model, defined mechanistic pathway with binding assay, multiple in vivo and in vitro validations","pmids":["32814052"],"is_preprint":false},{"year":2006,"finding":"A C-to-T polymorphism at position c.-292 in the ALOX15 promoter creates a novel binding site for the transcription factor SPI1 (PU.1), resulting in ~3-fold higher ALOX15 transcription in macrophages that constitutively express SPI1; mutation of the SPI1 core binding site abolishes higher transcriptional activity.","method":"Promoter transcription assays, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis, primary human macrophage mRNA quantification","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1-2 — EMSA, reporter assay with mutagenesis, confirmed in primary human macrophages","pmids":["16320347"],"is_preprint":false},{"year":2009,"finding":"15-LOX-1 transcription is repressed in colon cancer cells through recruitment of the NuRD repressor complex (containing MTA1 and HDAC1) to the -120 to -391 region of the 15-LOX-1 promoter; HDAC inhibitors reduce NuRD recruitment and activate 15-LOX-1 transcription, while siRNA knockdown of MTA1 or HDAC1 activates 15-LOX-1.","method":"Chromatin immunoprecipitation, siRNA knockdown, luciferase reporter assays, HDAC inhibitor treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — ChIP, reporter assays, RNAi knockdown with multiple orthogonal methods","pmids":["19198625"],"is_preprint":false},{"year":2006,"finding":"GATA-6 overexpression contributes to transcriptional silencing of 15-LOX-1 in colon cancer cells; GATA-6 siRNA knockdown contributes to restoring 15-LOX-1 expression and inducing apoptosis when combined with NSAID or HDAC inhibitor treatment.","method":"GATA-6 siRNA transfection, gene expression analysis, cell proliferation and apoptosis assays in colon cancer cells","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with functional readout, but GATA-6 knockdown alone insufficient; combination required","pmids":["17167069"],"is_preprint":false},{"year":2014,"finding":"Homozygous Alox15 deficiency does not rescue embryonic lethality of mice expressing catalytically inactive Gpx4 (Sec46Ala), indicating that Alox15 pro-oxidative activity is not the primary driver of lethality caused by loss of Gpx4 catalytic function.","method":"Genetic epistasis via crossbreeding Gpx4 knock-in and Alox15 knockout mice, embryonic viability assessment","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in a rigorous double-knockout/knock-in system","pmids":["25313597"],"is_preprint":false},{"year":2016,"finding":"Systemic inactivation of the Alox15 gene in male mice heterozygous for catalytically inactive Gpx4 (Sec46Ala) normalizes sperm motility, midpiece structure, and fertility, demonstrating that ALOX15 pro-oxidative activity directly counteracts Gpx4-dependent antioxidant protection in sperm.","method":"Genetic epistasis: crossbreeding Sec46Ala-Gpx4+/- mice with Alox15-/- mice, sperm motility analysis, fertility assessment, structural EM","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — rigorous genetic epistasis with functional rescue in vivo","pmids":["27634046"],"is_preprint":false},{"year":2010,"finding":"Alox15 (15-lipoxygenase) in sperm cytoplasmic droplets is required for normal epididymal sperm maturation and cytoplasmic droplet migration; Alox15-null males retain cytoplasmic droplets with intact mitochondria, unlike wild-type where droplets contain only hollow membrane vesicles.","method":"Differential interference contrast microscopy, transmission electron microscopy of Alox15-knockout vs. wild-type sperm","journal":"Cell and tissue research","confidence":"High","confidence_rationale":"Tier 2 — KO with defined ultrastructural and functional phenotype","pmids":["20449608"],"is_preprint":false},{"year":2010,"finding":"ALOX15 disruption in hyperlipidemic ApoE-/- mice reduces hepatic steatosis, inflammation, and insulin resistance; absence of Alox15 upregulates insulin receptor substrate-2, exerts opposing effects on JNK and AMPK phosphorylation, and protects hepatocytes from TNFα-induced apoptosis.","method":"Double-knockout mouse model (ApoE-/-/Alox15-/-), gene expression, phosphorylation assays, isolated hepatocyte apoptosis assay","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 — double-KO with molecular pathway analysis and ex vivo validation","pmids":["20967760"],"is_preprint":false},{"year":2022,"finding":"Vagus nerve stimulation (VNS) promotes resolution of inflammation in zymosan-induced peritonitis by increasing specialized proresolving mediators (SPMs) from the DHA and DPA metabolomes; this effect is abolished in Alox15-deficient mice, placing Alox15 as a required mediator of VNS-driven SPM biosynthesis.","method":"Electrical VNS in Alox15-knockout mice, lipid mediator metabololipidomics, peritonitis model","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (KO) combined with lipidomics in well-controlled in vivo model","pmids":["35622894"],"is_preprint":false},{"year":2021,"finding":"The anti-colitis protective effect of elevated n-3 PUFA tissue status in fat1 transgenic mice requires Alox15; Alox15 deficiency counteracts protection by suppressing 15-HEPE formation, and intraperitoneal 15S-HEPE treatment alone protects wild-type mice from colitis.","method":"Fat1 transgenic × Alox15-/- crossbreeding, DSS and TNBS colitis models, lipid mediator analysis, 15-HEPE administration","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with product rescue experiment","pmids":["33710695"],"is_preprint":false},{"year":2018,"finding":"Female Alox15-/- mice are protected from DSS-induced colitis; mechanistically, the major Alox15 product in mice (12S-HETE) enantioselectively compromises transepithelial electric resistance and reduces ZO-1 tight junction protein expression in colon epithelial cells, while human ALOX15 transgenic overexpression intensifies colitis.","method":"Alox15 KO mice, DSS colitis model, in vitro transepithelial resistance assay with exogenous 12S-HETE, ZO-1 expression analysis, transgenic overexpression","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 — KO, transgenic OE, and in vitro mechanistic assay with defined lipid mediator","pmids":["29702245"],"is_preprint":false},{"year":2013,"finding":"12/15-LO (Alox15) is expressed in macrophages but not B or T cells in NOD mice; Alox15 deletion reduces proinflammatory cytokine expression in macrophages and prevents diabetes transfer by splenocytes, while also maintaining islet transcription factor expression and beta cell mass.","method":"qRT-PCR of immune cell subsets, NOD-Alox15null mouse, adoptive transfer assay, beta cell mass measurement","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with adoptive transfer epistasis, cell-type-specific expression defined","pmids":["23437231"],"is_preprint":false},{"year":2017,"finding":"ALOX15 upregulation in the liver produces 13-HODE from linoleic acid, which induces oxidative stress, ER stress, and apoptosis in hepatocytes; ALOX15 knockout prevents alcohol-induced liver damage, and linoleic acid (not ethanol or acetaldehyde) induces ALOX15 expression in hepatocytes.","method":"ALOX15 knockout mice, pharmacologic inhibitor (PD146176), hepatocyte culture with 13-HODE, ALOX15 induction assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — KO mouse, pharmacologic inhibition, and in vitro mechanistic dissection","pmids":["28827690"],"is_preprint":false},{"year":2020,"finding":"Efferocytosis potentiates ALOX15 expression in alternatively activated human macrophages via LXR activation: AC uptake upregulates LXR-dependent gene expression (suppressed by NPC1 inhibition), and LXR/IL-13 co-stimulation enhances ALOX15 expression and increases SPM precursor (15-HETE, 17-HDHA, resolvin D5) synthesis; LXRα/β silencing attenuates this potentiation.","method":"Primary human macrophage efferocytosis assay, LXR agonist treatment, NPC1 inhibition, LXRα/β siRNA silencing, global transcriptome analysis, LC-MS/MS lipid mediator quantification","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — primary human macrophages, RNAi, pharmacologic tools, and lipidomics with multiple orthogonal approaches","pmids":["33177619"],"is_preprint":false},{"year":2007,"finding":"A coding SNP in ALOX15 (T560M) results in a ~20-fold reduction in catalytic activity in vitro, creating a near-null variant of human 12/15-LOX.","method":"ALOX15 resequencing, in vitro catalytic activity assay of 560M vs. 560T variants","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic characterization of the variant","pmids":["17959182"],"is_preprint":false},{"year":2017,"finding":"Alox15 in the prefrontal cortex metabolizes DHA to 17S-hydroxy-DHA, which is converted to resolvin D1; inhibition or antisense knockdown of Alox15 in the prefrontal cortex reduces resolvin D1 levels, blocks hippocampo-prefrontal cortical LTP, and impairs spatial working memory.","method":"RT-PCR, Western blot, immunohistochemistry, immuno-electron microscopy, LC-MS quantification, Alox15 inhibition/antisense knockdown in vivo, T-maze and LTP assays","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 — localization with functional consequence, loss-of-function with defined biochemical and behavioral readouts","pmids":["28181190"],"is_preprint":false},{"year":2018,"finding":"Hypoxic cardiac fibroblasts from failing hearts increase ALOX15 expression and produce 15-HETE; conditioned medium from these fibroblasts decreases beating frequency of human iPSC-derived cardiomyocytes in an ALOX15-dependent manner.","method":"Cardiac fibroblast isolation, hypoxic culture, gene expression, 15-HETE measurement, conditioned medium transfer to iPS-cardiomyocytes, calcium imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — functional paracrine assay with ALOX15-dependency, single lab","pmids":["30138423"],"is_preprint":false},{"year":2017,"finding":"Alox15 expression in mouse prefrontal cortex is regulated epigenetically by histone acetylation; HDAC inhibitors (trichostatin A, sodium butyrate) and class I-specific HDAC inhibitors upregulate Alox15, while the p300 HAT inhibitor C646 modulates this upregulation, implicating p300 HAT in differentiation-associated Alox15 upregulation in neurons.","method":"HDAC inhibitor treatment of SH-SY5Y cells, p300 HAT inhibitor co-treatment, retinoic acid differentiation, mRNA expression analysis, primary cortical neuron development time-course","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacologic manipulation with expression readout, no direct ChIP or mechanistic confirmation of p300 binding to Alox15 locus","pmids":["29235036"],"is_preprint":false},{"year":2004,"finding":"15-LOX-1 overexpression in HCT-116 colon cancer cells induces ERK1/2 phosphorylation, decreases p21(Cip/WAF1) expression, and increases cell growth; the LOX inhibitor NDGA reverses these effects, identifying 13-S-HODE as the active metabolite mediating MEK-ERK1/2 signaling.","method":"15-LOX-1 transfection, ERK1/2 phosphorylation assay, p21 expression analysis, LOX inhibitor (NDGA) treatment, sodium butyrate/13-S-HODE treatment","journal":"Prostaglandins & other lipid mediators","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression with defined signaling readout, pharmacologic dissection; single lab","pmids":["15165036"],"is_preprint":false},{"year":2010,"finding":"Selenoprotein P (SelP) exhibits in vitro lipid hydroperoxidase activity against 15-HpETE produced by ALOX15, attenuating 15-HpETE oxidation in cellular assays and in a transcellular model where ALOX15 is metabolically active, establishing SelP as an extracellular antioxidant defense against ALOX15 products.","method":"In vitro hydroperoxidase assay, cellular 15-HpETE oxidation assay, transcellular assay with metabolically active 15-LOX-1","journal":"Prostaglandins, leukotrienes, and essential fatty acids","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic assay confirmed in cellular context; modest activity noted","pmids":["20826080"],"is_preprint":false},{"year":2022,"finding":"SSAT1 activation upregulates ALOX15 expression in primary cortical neurons; SSAT1 knockdown downregulates ALOX15 and reduces ferroptosis (lipid hydroperoxide production, viability loss) in neurons treated with oxidative stress; SSAT1 overexpression decreases GPX4 and SLC7A11 expression; ALOX15 inhibitor PD146176 partially reverses SSAT1-induced ferroptosis, placing ALOX15 downstream of SSAT1 in neuronal ferroptosis.","method":"SSAT1 siRNA/overexpression in primary neurons, ALOX15 inhibitor treatment, viability assay, lipid hydroperoxide measurement, GPX4/SLC7A11 expression analysis, rat I/R model","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi epistasis and pharmacologic inhibition with defined molecular readouts; single lab","pmids":["35090880"],"is_preprint":false},{"year":2023,"finding":"DHODH inhibits the P53/ALOX15 signaling pathway in neurons to reduce ferroptosis after spinal cord injury; DHODH decreases P53 expression, which in turn suppresses ALOX15 expression and reduces lipid peroxide production and mitochondrial damage.","method":"Rat SCI model, erastin-induced PC12 cells, molecular and histological ferroptosis assessment, DHODH modulation, P53/ALOX15 pathway analysis","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro models with pathway analysis; pathway placement by epistasis","pmids":["36942513"],"is_preprint":false},{"year":2024,"finding":"FGF21 deficiency leads to abnormal activation of the ALOX15/15-HETE pathway, triggering innate immunity-dominated pro-inflammatory responses in liver grafts during ischemia/reperfusion injury; pharmacological FGF21 administration suppresses this pathway and protects against hepatic I/R injury.","method":"Male mouse models of hepatic I/R injury and orthotopic LT, FGF21-deficient mice, arachidonic acid metabolomics, pharmacologic FGF21 administration","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic deficiency model with metabolomic pathway validation and pharmacologic rescue; single lab","pmids":["39362839"],"is_preprint":false},{"year":2024,"finding":"MAFB transcription factor in macrophages directly regulates ALOX15 expression during ischemic acute kidney injury; macrophage-specific Mafb deficiency significantly decreases Alox15 mRNA and protein in infiltrating macrophages; in vitro, MAFB regulates Alox15 expression under the COX-2/PGE2/EP4 pathway, mediating a lipid mediator class switch from pro-inflammatory to proresolving mediators.","method":"Macrophage-specific Mafb-KO mice, ischemia-reperfusion AKI model, mRNA/protein analysis, in vitro PGE2/EP4 pathway assay, lipid mediator profiling","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — macrophage-specific KO with in vitro mechanistic confirmation; single lab","pmids":["39230290"],"is_preprint":false},{"year":2024,"finding":"ALOX15 forms a complex with PEBP1 (phosphatidylethanolamine-binding protein 1) in macrophages under psychological stress, mediating membrane phospholipid peroxidation; disruption of this ALOX15/PEBP1 interaction (by DZXY components) inhibits phospholipid peroxidation and restores macrophage phagocytic capacity. Confirmed by co-immunoprecipitation and microscale thermophoresis.","method":"LC-MS/MS phospholipidomics, co-immunoprecipitation, microscale thermophoresis (MST), molecular docking, activity verification, flow cytometry","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and MST biophysical binding confirmed; functional consequences validated in vivo and in vitro","pmids":["38492368"],"is_preprint":false},{"year":2021,"finding":"Conformational heterogeneity of rabbit ALOX15 and human ALOX15B: native PAGE shows two conformers with distinct electrophoretic mobilities; MD simulations indicate substrate-bound geometry at the active site affects dimer interface geometry; Gln596 mutations impair allosteric properties as shown by kinetics and MD.","method":"Native PAGE, site-directed mutagenesis, MD simulations, in silico docking, kinetic measurements","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 — structural and kinetic analysis with mutagenesis; single lab","pmids":["33807076"],"is_preprint":false},{"year":2020,"finding":"Gln596 in mammalian ALOX15 does not directly interact with the carboxylate of arachidonic acid; instead, mutations at Gln596 destabilize ALOX15 secondary and tertiary structure by disrupting local electrostatic interactions, and impair allosteric properties by altering dimer interface geometry.","method":"Site-directed mutagenesis, in silico substrate docking, molecular dynamics simulations, enzyme kinetics, structural assays of rabbit and human ALOX15","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis with structural and kinetic readouts; computational validation; single lab","pmids":["32151768"],"is_preprint":false},{"year":2022,"finding":"N-substituted 5-(1H-indol-2-yl)-2-methoxyaniline derivatives are allosteric inhibitors that selectively inhibit the linoleate oxygenase activity of rabbit and human ALOX15 without affecting arachidonic acid oxygenation; MD simulations using a dimer model suggest inhibitor binding at one monomer active site induces conformational changes in the other monomer impairing productive linoleic acid complex formation.","method":"Synthesis of inhibitor series, steady-state enzyme kinetics, mutagenesis studies, molecular dynamics simulations of ALOX15 dimer","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro kinetics, mutagenesis, and MD simulations defining allosteric mechanism; single lab","pmids":["35073698"],"is_preprint":false},{"year":2017,"finding":"Mutagenesis of Val418 and Val419 sequence determinants in porcine ALOX15 (arachidonic acid 12-lipoxygenating) converts it to a dominantly 15-lipoxygenating enzyme; QM/MM calculations show that the Val418Ile+Val419Met double mutant lowers the energy barrier for 15-lipoxygenation relative to 12-lipoxygenation, altering the catalytic mechanism of initial hydrogen abstraction.","method":"Site-directed mutagenesis, docking and MD simulations, QM/MM calculations, in vitro enzymatic assay","journal":"Chemistry (Weinheim)","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with QM/MM mechanistic characterization of hydrogen abstraction","pmids":["29154477"],"is_preprint":false},{"year":2008,"finding":"Induction of Alox15 in the intestine of iron-deficient rats leads to production of biologically active lipid molecules (12-HETE, 13-HODE, 13-HOTE) as shown by HPLC analysis, perturbing intestinal lipid homeostasis.","method":"Gene chip studies, TaqMan RT-PCR, polyclonal antibody protein detection, HPLC lipid analysis in iron-deficient rats and Belgrade rats","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — two independent iron-deficiency models with protein and product confirmation; single lab","pmids":["18258795"],"is_preprint":false},{"year":2011,"finding":"ALOX15 expression in colon cancer cells suppresses HIF-1α protein expression and stability under hypoxia, inhibiting VEGF expression, angiogenesis, and cancer cell migration and invasion.","method":"15-LOX-1 reexpression in multiple colon cancer cell lines (HCT116, HT29LMM, LoVo), HIF-1α stability assay, VEGF measurement, migration/invasion assay, angiogenesis assay","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function in multiple cell lines with defined molecular and functional readouts; single lab","pmids":["24634093"],"is_preprint":false},{"year":2023,"finding":"Macrophage-derived exosomes containing miRNA-660-5p are transported into cervical cancer cells where miRNA-660-5p attenuates ALOX15 expression to suppress ferroptosis; upregulation of miRNA-660-5p in macrophages is driven by autocrine IL-4/IL-13-activated STAT6 pathway.","method":"Exosome isolation and transfer, miRNA-660-5p overexpression/knockdown, ALOX15 expression analysis, ferroptosis assays, STAT6 pathway inhibition, in vivo tumor models","journal":"Acta pharmaceutica Sinica B","confidence":"Medium","confidence_rationale":"Tier 2 — exosome transfer with miRNA mechanism and STAT6 pathway placement; in vivo validation","pmids":["37425043"],"is_preprint":false},{"year":2025,"finding":"ALOX15 aggravates MASLD/steatotic liver disease via the PPARγ/CD36 axis: ALOX15 overexpression increases fatty acid uptake and triglyceride accumulation; PPARγ antagonist GW9662 or CD36 inhibitor blocks ALOX15-mediated lipid accumulation; liraglutide (GLP-1RA) improves hepatic lipid accumulation by suppressing the ALOX15/PPARγ/CD36 pathway.","method":"ALOX15 lentiviral overexpression and siRNA knockdown in HepG2 cells, transcriptomics, metabolomics, pharmacologic inhibition of PPARγ/CD36, HFD/STZ mouse model","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression and KD with pathway pharmacologic validation in vitro and in vivo; single lab","pmids":["39815992"],"is_preprint":false},{"year":2023,"finding":"Bmal1 in AML cells recruits EZH2 to the EBF3 promoter, enhancing its methylation and suppressing EBF3 expression; EBF3 binds the ALOX15 promoter to enhance ALOX15 expression, promoting ferroptosis; Bmal1 therefore suppresses ALOX15-mediated ferroptosis via EZH2/EBF3 axis.","method":"ChIP for EZH2 at EBF3 promoter, EBF3 ChIP at ALOX15 promoter, Bmal1 overexpression/knockdown, EBF3 knockdown, ferroptosis assays, xenograft model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for upstream regulatory events and ferroptosis readout in vivo; single lab","pmids":["37271497"],"is_preprint":false},{"year":2024,"finding":"PER1 binds the SREBF2 promoter to repress SREBF2 transcription; SREBF2 in turn binds the ALOX15 promoter to repress ALOX15 transcription; thus PER1 promotes ALOX15-mediated ferroptosis in granulosa cells in PCOS by removing SREBF2-mediated repression of ALOX15.","method":"ChIP-qPCR, promoter binding assays, PER1 overexpression, SREBF2 overexpression/knockdown, ALOX15 silencing, ferroptosis assays in granulosa cells","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for transcription factor binding at ALOX15 promoter, epistasis experiment; single lab","pmids":["38653359"],"is_preprint":false},{"year":2024,"finding":"DHI (dihydrotanshinone I) upregulates EGR1, leading to decreased DNMT1 expression, increased ALOX15 demethylation, and ALOX15-dependent ferroptosis induction in hepatic stellate cells; EGR1 is a direct pharmacological target of DHI confirmed by molecular docking.","method":"Transcriptome sequencing, qRT-PCR, Western blot, DNMT1 overexpression, ALOX15 siRNA, methylation analysis, molecular docking","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — epigenetic mechanism with transcriptomics and functional validation; single lab","pmids":["39675198"],"is_preprint":false},{"year":2024,"finding":"Lachnospiraceae-derived pyruvate inhibits ALOX15 expression and reduces ferroptosis in donor livers during transplantation I/R injury; reduced nuclear translocation of Foxo3 further suppresses ALOX15 expression, identifying a Foxo3-Alox15 axis.","method":"Multi-omics, Lachnospiraceae treatment in rat LT models, Foxo3 nuclear translocation analysis, Alox15 expression measurement, ferroptosis assays","journal":"Gut microbes","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics with mechanistic pathway validation in vivo; single lab","pmids":["39882747"],"is_preprint":false},{"year":2018,"finding":"Spinal microglial ALOX15 (15-LOX-1) mediates TLR4-dependent hepoxilin production and tactile allodynia; intrathecal TLR4 activation increases 15-LOX-1 expression in primary spinal microglia (but not astrocytes) and hepoxilin production; selective 15-LOX-1 inhibitors (ML127, ML351) reduce activity of rat 15-LOX-1 expressed in HEK-293T cells and completely abrogate TLR4-induced allodynia.","method":"Intrathecal KLA administration, primary spinal microglia/astrocyte culture, selective antibody targeting, HEK-293T heterologous expression with inhibitor assay, in vivo pharmacology","journal":"Pain","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic inhibition, cell-type-specific expression, and in vivo pharmacologic rescue with selective inhibitors","pmids":["30130298"],"is_preprint":false},{"year":2024,"finding":"HIF1A, whose transcription is enhanced by lactate-driven histone lactylation at its promoter, activates the ACSL4/LPCAT3/ALOX15 pathway to induce ferroptosis in severe acute pancreatitis; sh-HIF1A reduces ALOX15 expression and ferroptosis markers; ChIP-qPCR confirms HIF1A promoter binding.","method":"sh-HIF1A mice, SAP mouse model, ChIP-qPCR, luciferase reporter, Western blot, qPCR, ferroptosis marker measurement","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KD and ChIP for HIF1A at ALOX15 pathway; pathway placement by epistasis; single lab","pmids":["39676583"],"is_preprint":false}],"current_model":"ALOX15 is a lipid-peroxidizing enzyme that oxygenates polyunsaturated fatty acids (arachidonic acid, linoleic acid, DHA, EPA) to generate bioactive hydroperoxy lipids (15-HpETE, 13-HODE, 12-HETE, 15-HEPE, resolvins, lipoxins); its reaction specificity (12- vs. 15-lipoxygenating) is determined by conserved triad residues and evolved in higher primates toward 15-lipoxygenation to optimize lipoxin and SPM biosynthesis; in ferroptosis, ALOX15 directly peroxidizes PUFA-phospholipids (acting downstream of p53/SAT1 and upstream of GPX4/PGC1α degradation pathways); it is transcriptionally regulated by SPI1, NuRD/HDAC complexes, GATA-6, MAFB, and epigenetic histone acetylation; it forms a functional complex with PEBP1 to redirect peroxidase activity toward membrane phospholipids; it suppresses Wnt/β-catenin signaling via PI3P peroxidation to inhibit LRP5 recycling; and it plays defined roles in erythropoiesis, sperm maturation, inflammation resolution, bone density, hepatic lipid metabolism, and neuropathic pain through cell-type-specific production of lipid mediators."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing ALOX15 as the principal linoleic acid oxygenase in colon cells resolved the question of which enzyme generates the pro-apoptotic mediator 13-S-HODE downstream of NSAIDs, linking ALOX15 catalytic activity directly to apoptosis induction.","evidence":"Enzymatic activity assays, pharmacologic inhibition with caffeic acid, and rescue with exogenous 13-S-HODE in colorectal cancer cell lines","pmids":["10904086"],"confidence":"High","gaps":["Upstream transcriptional mechanism by which NSAIDs induce ALOX15 was not defined","Whether 13-S-HODE acts through a specific receptor was not resolved"]},{"year":2004,"claim":"Demonstration that Alox15 knockout improves bone mineral density in mice established ALOX15 as a negative regulator of bone formation, revealing an unexpected physiological role beyond classical eicosanoid biology.","evidence":"Alox15 KO mouse crosses and pharmacologic inhibitor treatment with bone density and strength measurements","pmids":["14716014"],"confidence":"High","gaps":["The specific lipid mediator and downstream pathway by which ALOX15 suppresses osteoblast activity was not identified","Human genetic validation was lacking"]},{"year":2006,"claim":"Identification of SPI1 binding to a promoter polymorphism and NuRD/HDAC-mediated repression at the ALOX15 promoter established the first transcriptional regulatory mechanisms controlling cell-type-specific ALOX15 expression.","evidence":"EMSA, reporter assays with mutagenesis in macrophages (SPI1); ChIP, siRNA knockdown, and HDAC inhibitor treatment in colon cancer cells (NuRD)","pmids":["16320347","19198625","17167069"],"confidence":"High","gaps":["How SPI1 and NuRD regulatory circuits integrate in immune cells was not addressed","GATA-6 contribution required combination treatment, suggesting it is a co-factor rather than primary regulator"]},{"year":2007,"claim":"Characterization of the T560M near-null coding variant provided the first human genetic evidence that ALOX15 catalytic activity varies substantially in the population, with implications for disease susceptibility studies.","evidence":"Resequencing and in vitro catalytic activity assay of T560M vs. wild-type ALOX15","pmids":["17959182"],"confidence":"High","gaps":["Population frequency and clinical phenotypic consequences of T560M were not established","No structural explanation for the ~20-fold activity reduction was provided"]},{"year":2010,"claim":"Discovery that Alox15 is required for sperm cytoplasmic droplet remodeling and organelle clearance during epididymal maturation revealed a specialized developmental function in male germ cells, later confirmed by genetic epistasis with Gpx4.","evidence":"Alox15-KO sperm ultrastructural analysis by TEM; genetic epistasis with Gpx4 Sec46Ala heterozygotes restoring sperm motility and fertility","pmids":["20449608","27634046"],"confidence":"High","gaps":["The specific ALOX15-derived lipid mediator driving organelle clearance in sperm was not identified","Whether this function is conserved in human spermatogenesis is unknown"]},{"year":2010,"claim":"Double-KO studies showed Alox15 disruption protects against hepatic steatosis and insulin resistance in hyperlipidemic mice, establishing ALOX15 as a driver of hepatic lipid pathology through JNK/AMPK and IRS-2 modulation.","evidence":"ApoE−/−/Alox15−/− double-knockout mouse, phosphorylation assays, hepatocyte apoptosis assay","pmids":["20967760"],"confidence":"High","gaps":["The direct ALOX15 lipid mediator responsible for hepatic signaling was not fully defined","Applicability to non-hyperlipidemic hepatic disease was untested"]},{"year":2014,"claim":"Genetic epistasis showed that Alox15 deletion does not rescue Gpx4 catalytic-null embryonic lethality, establishing that ALOX15 is not the sole oxidative driver of Gpx4-dependent developmental lethality despite its role in ferroptosis.","evidence":"Crossbreeding of Gpx4 Sec46Ala knock-in with Alox15-KO mice, embryonic viability assessment","pmids":["25313597"],"confidence":"High","gaps":["Which other lipoxygenases or non-enzymatic pathways compensate in the Gpx4-null embryonic context was not determined"]},{"year":2015,"claim":"Systematic mutagenesis of triad determinants (Leu353, Ile593) and Val418/Val419 across species orthologs, combined with QM/MM calculations, resolved the structural basis of 12- vs. 15-lipoxygenation specificity and demonstrated that ALOX15 evolved 15-lipoxygenating capability in higher primates to optimize lipoxin synthase activity.","evidence":"Recombinant mutagenesis, in vitro enzymatic assays across multiple orthologs, QM/MM calculations of hydrogen abstraction energy barriers","pmids":["25731857","27412860","29154477","28400162"],"confidence":"High","gaps":["Crystal structures of substrate-bound human ALOX15 confirming the QM/MM predictions are lacking","How positional specificity changes affect in vivo SPM profiles in primates was not tested"]},{"year":2017,"claim":"Localization and functional studies in prefrontal cortex established that ALOX15 converts DHA to 17S-HDHA/resolvin D1 in neurons, directly linking ALOX15 to synaptic plasticity (LTP) and spatial working memory.","evidence":"RT-PCR, immuno-EM localization, LC-MS quantification, in vivo Alox15 inhibition/antisense knockdown with T-maze and LTP electrophysiology","pmids":["28181190"],"confidence":"High","gaps":["The receptor through which resolvin D1 modulates LTP was not identified","Whether neuronal ALOX15 is relevant to human cognitive function is untested"]},{"year":2018,"claim":"Demonstration that spinal microglial ALOX15 mediates TLR4-dependent hepoxilin production and tactile allodynia identified a cell-type-specific pro-nociceptive role, with selective ALOX15 inhibitors (ML127, ML351) fully abrogating pain behavior.","evidence":"Primary spinal microglia culture, HEK-293T heterologous expression with selective inhibitors, intrathecal TLR4 activation model","pmids":["30130298"],"confidence":"High","gaps":["Whether ALOX15-dependent allodynia operates in chronic pain conditions beyond TLR4 activation was not explored","The hepoxilin receptor mediating nociception was not identified"]},{"year":2018,"claim":"Characterization of ALOX15 products (12S-HETE) compromising tight junction integrity (ZO-1) in colon epithelium, combined with KO protection from colitis, established a mechanism by which ALOX15 promotes intestinal barrier dysfunction.","evidence":"Alox15-KO and human ALOX15 transgenic mice in DSS colitis model, transepithelial resistance assay with enantioselective 12S-HETE","pmids":["29702245"],"confidence":"High","gaps":["The receptor or signaling pathway through which 12S-HETE reduces ZO-1 was not defined","Whether the protective vs. pro-resolving roles of ALOX15 in colitis are sex-dependent was not fully explored"]},{"year":2020,"claim":"Discovery that ALOX15 peroxidizes PI3P to generate PI3P-13-HODE, which disrupts SNX17-LRP5 binding, inhibits LRP5 recycling, and suppresses Wnt/β-catenin signaling, revealed a novel non-classical mechanism linking lipid peroxidation to endosomal sorting and tumor suppression.","evidence":"ALOX15 transgenic mouse intestine, APC-mutant model, PI3P-lipid binding assays, endosome tracking","pmids":["32814052"],"confidence":"High","gaps":["Whether PI3P peroxidation affects other PI3P-dependent endosomal cargo is unknown","Structural basis for loss of SNX17 binding to oxidized PI3P was not determined"]},{"year":2020,"claim":"Efferocytosis was shown to potentiate ALOX15 expression in human macrophages through LXR activation, linking phagocytic clearance of apoptotic cells to amplified SPM biosynthesis and establishing a feedforward resolution circuit.","evidence":"Primary human macrophage efferocytosis assay, LXR agonist and NPC1 inhibition, LXRα/β siRNA, LC-MS/MS lipid mediator profiling","pmids":["33177619"],"confidence":"High","gaps":["Whether LXR directly binds the ALOX15 promoter or acts indirectly was not resolved","The contribution of other LXR target genes to SPM amplification was not isolated"]},{"year":2021,"claim":"Genetic epistasis confirmed that the anti-colitis effect of elevated tissue n-3 PUFAs requires Alox15, with 15S-HEPE identified as a sufficient protective mediator, resolving the question of which enzyme converts dietary omega-3 fatty acids into bioactive anti-inflammatory products in vivo.","evidence":"Fat1 transgenic × Alox15-KO crossbreeding, DSS/TNBS colitis models, lipid mediator analysis, 15-HEPE rescue","pmids":["33710695"],"confidence":"High","gaps":["The receptor and signaling pathway through which 15S-HEPE protects from colitis was not identified"]},{"year":2022,"claim":"Multi-omics and chemogenetic studies established ALOX15 as the primary initiator of PUFA-phospholipid peroxidation (specifically PE-PUFAs) in cardiomyocytes during ischemia-reperfusion, positioning it as a 'burning point' for ferroptotic signaling.","evidence":"Multi-omics with chemogenetic approaches in animal and cellular models of cardiac I/R","pmids":["35970840"],"confidence":"High","gaps":["How ALOX15 is activated or stabilized specifically during ischemia-reperfusion was not mechanistically defined"]},{"year":2022,"claim":"ALOX15 was placed as a required mediator of vagus nerve stimulation-driven SPM biosynthesis, establishing the neuro-immune mechanism by which cholinergic anti-inflammatory signaling resolves inflammation through ALOX15-dependent lipid mediator production.","evidence":"Electrical VNS in Alox15-KO mice, lipid mediator metabololipidomics in zymosan peritonitis model","pmids":["35622894"],"confidence":"High","gaps":["The cell type mediating VNS-dependent ALOX15 activation was not identified","Whether VNS directly upregulates ALOX15 or increases substrate availability was not resolved"]},{"year":2023,"claim":"Identification that 15-HpETE promotes PGC1α binding to the E3 ligase RNF34, leading to PGC1α ubiquitin-dependent degradation and attenuated mitochondrial biogenesis, revealed a mechanistic link between ALOX15 catalytic products and mitochondrial dysfunction in ferroptotic cardiomyocytes.","evidence":"Myocardial-specific ALOX15 KO mice, co-IP of PGC1α-RNF34, metabolomics, pharmacologic inhibition with ML351","pmids":["36987924"],"confidence":"High","gaps":["Whether 15-HpETE acts directly on PGC1α or RNF34 to promote their interaction is not structurally resolved","Generalizability of this mechanism to non-cardiac ferroptosis contexts is untested"]},{"year":2024,"claim":"MAFB was identified as a direct transcriptional regulator of ALOX15 in macrophages during ischemic AKI, operating downstream of the COX-2/PGE2/EP4 pathway to mediate a lipid mediator class switch from pro-inflammatory to proresolving, answering how macrophage phenotype transitions engage ALOX15 transcription.","evidence":"Macrophage-specific Mafb-KO mice, AKI model, in vitro PGE2/EP4 pathway assay, lipid mediator profiling","pmids":["39230290"],"confidence":"Medium","gaps":["Whether MAFB binds the ALOX15 promoter directly was not confirmed by ChIP","Generalizability beyond renal I/R macrophages is unknown"]},{"year":2024,"claim":"Co-immunoprecipitation and microscale thermophoresis confirmed that ALOX15 forms a functional complex with PEBP1 in macrophages, redirecting its peroxidase activity toward membrane phospholipids; disruption of this complex inhibits phospholipid peroxidation and ferroptosis.","evidence":"Co-IP, MST biophysical binding, LC-MS/MS phospholipidomics, molecular docking, in vivo and in vitro functional verification","pmids":["38492368"],"confidence":"Medium","gaps":["Structural basis of the ALOX15-PEBP1 interface in the context of membrane substrates is not resolved","Independent replication in a second laboratory is needed"]},{"year":null,"claim":"Key unresolved questions include the crystal structure of substrate-bound human ALOX15, the identity of receptors for many ALOX15-derived lipid mediators (hepoxilins, 15-HEPE, 13-S-HODE), the mechanism by which ALOX15 is selectively activated during ischemia, and how the pro-inflammatory versus pro-resolving functions of ALOX15 are spatiotemporally segregated within the same cell type.","evidence":"","pmids":[],"confidence":"Low","gaps":["No substrate-bound crystal structure of human ALOX15 exists","Receptors for many ALOX15 products remain unidentified","Spatiotemporal regulation of pro- vs. anti-inflammatory ALOX15 activity in single cells is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[2,4,5,6,7,35]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,6,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13,31]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,31]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,4,5,6,7,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,27,28,40,41]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,16,18,20,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,25]}],"complexes":["ALOX15-PEBP1 complex"],"partners":["PEBP1","GPX4","RNF34","SPI1","MTA1","HDAC1","MAFB","LRP5"],"other_free_text":[]},"mechanistic_narrative":"ALOX15 is a non-heme iron dioxygenase that oxygenates polyunsaturated fatty acids—both free and esterified in membrane phospholipids—to generate bioactive lipid mediators including 15-HpETE, 13-HODE, 12-HETE, 15-HEPE, and resolvin D1, with positional specificity (12- vs. 15-lipoxygenation) governed by conserved triad residues that evolved in higher primates to optimize 15-lipoxygenation and lipoxin synthase activity [PMID:27412860, PMID:25731857, PMID:29154477]. Through these lipid products, ALOX15 drives ferroptotic cell death by peroxidizing PUFA-phosphatidylethanolamines—acting downstream of p53/SSAT1 and upstream of GPX4—and forms a complex with PEBP1 to redirect peroxidase activity toward membrane phospholipids; its metabolite 15-HpETE also promotes PGC1α ubiquitin-dependent degradation via RNF34 to attenuate mitochondrial biogenesis [PMID:35970840, PMID:36987924, PMID:35090880, PMID:38492368]. ALOX15 mediates inflammation resolution by serving as the required biosynthetic enzyme for specialized proresolving mediators (SPMs) from DHA and EPA in macrophages, a function potentiated by efferocytosis-driven LXR activation and regulated by transcription factors including SPI1, MAFB, NuRD/HDAC complexes, and GATA-6 [PMID:35622894, PMID:33710695, PMID:33177619, PMID:16320347, PMID:19198625, PMID:39230290]. In addition, ALOX15 suppresses Wnt/β-catenin signaling by peroxidizing PI3P to impair LRP5 endosomal recycling, regulates peak bone density as a negative regulator, is required for normal sperm cytoplasmic droplet remodeling, and contributes to hepatic lipid metabolism and neuropathic pain through cell-type-specific lipid mediator production [PMID:32814052, PMID:14716014, PMID:20449608, PMID:20967760, PMID:30130298]."},"prefetch_data":{"uniprot":{"accession":"P16050","full_name":"Polyunsaturated fatty acid lipoxygenase ALOX15","aliases":["12/15-lipoxygenase","Arachidonate 12-lipoxygenase, leukocyte-type","12-LOX","Arachidonate 15-lipoxygenase","15-LOX","15-LOX-1","Arachidonate omega-6 lipoxygenase","Hepoxilin A3 synthase Alox15","Linoleate 13S-lipoxygenase"],"length_aa":662,"mass_kda":74.8,"function":"Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators (PubMed:17052953, PubMed:1944593, PubMed:24282679, PubMed:25293588, PubMed:32404334, PubMed:8334154). It inserts peroxyl groups at C12 or C15 of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) producing both 12-hydroperoxyeicosatetraenoate/12-HPETE and 15-hydroperoxyeicosatetraenoate/15-HPETE (PubMed:17052953, PubMed:1944593, PubMed:24282679, PubMed:8334154). It may then act on 12-HPETE to produce hepoxilins, which may show pro-inflammatory properties (By similarity). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate/13-HPODE (PubMed:8334154). May participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs)like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets (PubMed:32404334). Can convert epoxy fatty acids to hydroperoxy-epoxides derivatives followed by an intramolecular nucleophilic substitution leading to the formation of monocyclic endoperoxides (PubMed:25293588). Plays an important role during the maintenance of self-tolerance by peroxidizing membrane-bound phosphatidylethanolamine which can then signal the sorting process for clearance of apoptotic cells during inflammation and prevent an autoimmune response. In addition to its role in the immune and inflammatory responses, this enzyme may play a role in epithelial wound healing in the cornea through production of lipoxin A4 (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1; 10R,17S-HDHA), both lipid autacoids exhibit anti-inflammatory and neuroprotective properties. Furthermore, it may regulate actin polymerization which is crucial for several biological processes such as the phagocytosis of apoptotic cells. It is also implicated in the generation of endogenous ligands for peroxisome proliferator activated receptor (PPAR-gamma), hence modulating macrophage development and function. It may also exert a negative effect on skeletal development by regulating bone mass through this pathway. As well as participates in ER stress and downstream inflammation in adipocytes, pancreatic islets, and liver (By similarity). Finally, it is also involved in the cellular response to IL13/interleukin-13 (PubMed:21831839)","subcellular_location":"Cytoplasm, cytosol; Cell membrane; Lipid droplet","url":"https://www.uniprot.org/uniprotkb/P16050/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALOX15","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ALOX15","total_profiled":1310},"omim":[{"mim_id":"603697","title":"ARACHIDONATE 15-LIPOXYGENASE, SECOND TYPE; ALOX15B","url":"https://www.omim.org/entry/603697"},{"mim_id":"208550","title":"ASTHMA, NASAL POLYPS, AND ASPIRIN INTOLERANCE","url":"https://www.omim.org/entry/208550"},{"mim_id":"164160","title":"LEPTIN; LEP","url":"https://www.omim.org/entry/164160"},{"mim_id":"152392","title":"ARACHIDONATE 15-LIPOXYGENASE; ALOX15","url":"https://www.omim.org/entry/152392"},{"mim_id":"152391","title":"ARACHIDONATE 12-OXIDOREDUCTASE; ALOX12","url":"https://www.omim.org/entry/152391"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":35.2},{"tissue":"fallopian tube","ntpm":12.0}],"url":"https://www.proteinatlas.org/search/ALOX15"},"hgnc":{"alias_symbol":["15-LOX-1"],"prev_symbol":[]},"alphafold":{"accession":"P16050","domains":[{"cath_id":"1.20.245.10","chopping":"152-167_359-543_602-643","consensus_level":"medium","plddt":97.7454,"start":152,"end":643}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16050","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16050-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16050-F1-predicted_aligned_error_v6.png","plddt_mean":95.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALOX15","jax_strain_url":"https://www.jax.org/strain/search?query=ALOX15"},"sequence":{"accession":"P16050","fasta_url":"https://rest.uniprot.org/uniprotkb/P16050.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16050/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16050"}},"corpus_meta":[{"pmid":"36987924","id":"PMC_36987924","title":"Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis.","date":"2023","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/36987924","citation_count":324,"is_preprint":false},{"pmid":"30472260","id":"PMC_30472260","title":"Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies.","date":"2018","source":"Progress in lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/30472260","citation_count":280,"is_preprint":false},{"pmid":"35970840","id":"PMC_35970840","title":"ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage.","date":"2022","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35970840","citation_count":219,"is_preprint":false},{"pmid":"14716014","id":"PMC_14716014","title":"Regulation of bone mass in mice by the lipoxygenase gene Alox15.","date":"2004","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14716014","citation_count":218,"is_preprint":false},{"pmid":"26216303","id":"PMC_26216303","title":"Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15).","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26216303","citation_count":173,"is_preprint":false},{"pmid":"10904086","id":"PMC_10904086","title":"15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells.","date":"2000","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/10904086","citation_count":150,"is_preprint":false},{"pmid":"25313597","id":"PMC_25313597","title":"Expression of inactive glutathione peroxidase 4 leads to embryonic lethality, and inactivation of the Alox15 gene does not rescue such knock-in mice.","date":"2014","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25313597","citation_count":88,"is_preprint":false},{"pmid":"16556493","id":"PMC_16556493","title":"Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.","date":"2006","source":"Prostaglandins, leukotrienes, and essential fatty acids","url":"https://pubmed.ncbi.nlm.nih.gov/16556493","citation_count":83,"is_preprint":false},{"pmid":"28400162","id":"PMC_28400162","title":"Mammalian ALOX15 orthologs exhibit pronounced dual positional specificity with docosahexaenoic acid.","date":"2017","source":"Biochimica et biophysica acta. 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reviews","url":"https://pubmed.ncbi.nlm.nih.gov/37154013","citation_count":7,"is_preprint":false},{"pmid":"38030974","id":"PMC_38030974","title":"Knock-in mice expressing a humanized arachidonic acid 15-lipoxygenase (Alox15) carry a partly dysfunctional erythropoietic system.","date":"2023","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/38030974","citation_count":7,"is_preprint":false},{"pmid":"22301860","id":"PMC_22301860","title":"Association of ALOX15 gene polymorphisms with obesity-related phenotypes in Chinese nuclear families with male offspring.","date":"2012","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/22301860","citation_count":7,"is_preprint":false},{"pmid":"22668814","id":"PMC_22668814","title":"Association of ALOX12 and ALOX15 gene polymorphisms with age at menarche and natural menopause in Chinese women.","date":"2012","source":"Menopause (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22668814","citation_count":7,"is_preprint":false},{"pmid":"32606775","id":"PMC_32606775","title":"Eicosapentaenoic acid's metabolism of 15-LOX-1 promotes the expression of miR-101 thus inhibits Cox2 pathway in colon cancer.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32606775","citation_count":7,"is_preprint":false},{"pmid":"38213304","id":"PMC_38213304","title":"Development of novel ALOX15 inhibitors combining dual machine learning filtering and fragment substitution optimisation approaches, molecular docking and dynamic simulation methods.","date":"2024","source":"Journal of enzyme inhibition and medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38213304","citation_count":6,"is_preprint":false},{"pmid":"38818906","id":"PMC_38818906","title":"Silencing HEATR1 Rescues Cisplatin Resistance of Non-small Cell Lung Cancer by Inducing Ferroptosis via the p53/SAT1/ALOX15 Axis.","date":"2025","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/38818906","citation_count":6,"is_preprint":false},{"pmid":"39230290","id":"PMC_39230290","title":"MAFB in Macrophages Regulates Prostaglandin E2-Mediated Lipid Mediator Class Switch through ALOX15 in Ischemic Acute Kidney Injury.","date":"2024","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/39230290","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56325,"output_tokens":11125,"usd":0.167925},"stage2":{"model":"claude-opus-4-6","input_tokens":15160,"output_tokens":5050,"usd":0.303075},"total_usd":0.471,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"ALOX15 metabolite 15-HpETE promotes binding of PGC1α to the ubiquitin ligase RNF34, leading to ubiquitin-dependent degradation of PGC1α, attenuated mitochondrial biogenesis, and cardiomyocyte ferroptosis during myocardial ischemia-reperfusion injury.\",\n      \"method\": \"Loss/gain-of-function mouse models, metabolomics, co-immunoprecipitation, myocardial-specific knockout, pharmacologic inhibition (ML351)\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal mechanistic experiments with KO mice, metabolomics, co-IP, and pharmacologic rescue in a defined disease model\",\n      \"pmids\": [\"36987924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALOX15 is the primary mediator of ischemia-provoked PUFA-phospholipid peroxidation (specifically oxidized PUFAs in phosphatidylethanolamines) in cardiomyocytes, acting as a 'burning point' that initiates ferroptotic signals during reperfusion.\",\n      \"method\": \"Multi-omics, chemogenetic approaches, animal and in vitro models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with chemogenetic confirmation, orthogonal validation\",\n      \"pmids\": [\"35970840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"15-LOX-1 (ALOX15) is the main enzyme for metabolizing linoleic acid to 13-S-HODE in colon cells; NSAIDs increase 15-LOX-1 protein expression and enzymatic activity, and 13-S-HODE is the proximate inducer of apoptosis — inhibiting 15-LOX-1 blocks NSAID-induced apoptosis, which is restored by exogenous 13-S-HODE.\",\n      \"method\": \"Enzymatic activity assay, protein expression (Western blot), pharmacologic inhibition (caffeic acid), rescue with exogenous 13-S-HODE in colorectal cancer cell lines\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic activity confirmed, loss-of-function with inhibitor, rescue with product, replicated in two cell lines\",\n      \"pmids\": [\"10904086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Alox15 (12/15-lipoxygenase) acts as a negative regulator of peak bone mineral density in mice; pharmacologic inhibitors of Alox15 improve bone density and strength in rodent osteoporosis models.\",\n      \"method\": \"Genetic crossbreeding with Alox15 knockout mice, pharmacologic inhibition, bone density/strength measurement\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse crossbreeding plus pharmacologic confirmation, replicated in two rodent models\",\n      \"pmids\": [\"14716014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The reaction specificity of mammalian ALOX15 evolved during late primate evolution: lower primates express 12-lipoxygenating ALOX15 orthologs, while higher primates (including humans) express 15-lipoxygenating enzymes; this switch optimizes lipoxin synthase activity, with 15-lipoxygenating variants having >5-fold higher lipoxin synthase activity. QM/MM calculations show lower energy barriers for C13-hydrogen abstraction (15-lipoxygenation) in rabbit ALOX15.\",\n      \"method\": \"Cloning and functional characterization of multiple ALOX15 orthologs, in vitro enzymatic assays, site-directed mutagenesis, molecular dynamics simulations, QM/MM calculations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution, mutagenesis, and QM/MM calculations across multiple species orthologs\",\n      \"pmids\": [\"27412860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mutagenesis of triad determinants (Leu353, Ile593) in rat Alox15 alters positional specificity for both free fatty acids and complex ester lipids; rat Alox15 and its 15-lipoxygenating Leu353Phe mutant can oxygenate ester lipids of biomembranes and HDL.\",\n      \"method\": \"Recombinant protein expression, multiple directed mutagenesis, in vitro enzymatic assays with free and esterified substrates\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with mutagenesis of key catalytic determinants\",\n      \"pmids\": [\"25731857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human ALOX15, chimpanzee, and orangutan orthologs exhibit pronounced dual positional specificity with DHA, forming similar amounts of 14- and 17-HpDHA; ALOX15 orthologs preferentially oxygenate DHA and EPA over arachidonic acid when supplied simultaneously.\",\n      \"method\": \"Recombinant expression of ALOX15 orthologs from eight mammalian species, in vitro enzymatic assays with multiple PUFA substrates\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — recombinant enzyme characterization across multiple orthologs with systematic substrate panels\",\n      \"pmids\": [\"28400162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"15-LOX-1 peroxidation of linoleic acid in phosphatidylinositol-3-phosphates (PI3P_LA) generates PI3P_13-HODE, which decreases PI3P binding to SNX17 and LRP5, inhibits LRP5 recycling from endosomes to the plasma membrane, increases LRP5 lysosomal degradation, and suppresses Wnt/β-catenin signaling to inhibit colorectal carcinogenesis.\",\n      \"method\": \"15-LOX-1 transgenic mouse intestinal expression, APC-mutant mouse model, in vitro mechanistic studies with PI3P-lipid binding assays, endosome tracking\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model, defined mechanistic pathway with binding assay, multiple in vivo and in vitro validations\",\n      \"pmids\": [\"32814052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A C-to-T polymorphism at position c.-292 in the ALOX15 promoter creates a novel binding site for the transcription factor SPI1 (PU.1), resulting in ~3-fold higher ALOX15 transcription in macrophages that constitutively express SPI1; mutation of the SPI1 core binding site abolishes higher transcriptional activity.\",\n      \"method\": \"Promoter transcription assays, electrophoretic mobility shift assay (EMSA), site-directed mutagenesis, primary human macrophage mRNA quantification\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — EMSA, reporter assay with mutagenesis, confirmed in primary human macrophages\",\n      \"pmids\": [\"16320347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"15-LOX-1 transcription is repressed in colon cancer cells through recruitment of the NuRD repressor complex (containing MTA1 and HDAC1) to the -120 to -391 region of the 15-LOX-1 promoter; HDAC inhibitors reduce NuRD recruitment and activate 15-LOX-1 transcription, while siRNA knockdown of MTA1 or HDAC1 activates 15-LOX-1.\",\n      \"method\": \"Chromatin immunoprecipitation, siRNA knockdown, luciferase reporter assays, HDAC inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, reporter assays, RNAi knockdown with multiple orthogonal methods\",\n      \"pmids\": [\"19198625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GATA-6 overexpression contributes to transcriptional silencing of 15-LOX-1 in colon cancer cells; GATA-6 siRNA knockdown contributes to restoring 15-LOX-1 expression and inducing apoptosis when combined with NSAID or HDAC inhibitor treatment.\",\n      \"method\": \"GATA-6 siRNA transfection, gene expression analysis, cell proliferation and apoptosis assays in colon cancer cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with functional readout, but GATA-6 knockdown alone insufficient; combination required\",\n      \"pmids\": [\"17167069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Homozygous Alox15 deficiency does not rescue embryonic lethality of mice expressing catalytically inactive Gpx4 (Sec46Ala), indicating that Alox15 pro-oxidative activity is not the primary driver of lethality caused by loss of Gpx4 catalytic function.\",\n      \"method\": \"Genetic epistasis via crossbreeding Gpx4 knock-in and Alox15 knockout mice, embryonic viability assessment\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in a rigorous double-knockout/knock-in system\",\n      \"pmids\": [\"25313597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Systemic inactivation of the Alox15 gene in male mice heterozygous for catalytically inactive Gpx4 (Sec46Ala) normalizes sperm motility, midpiece structure, and fertility, demonstrating that ALOX15 pro-oxidative activity directly counteracts Gpx4-dependent antioxidant protection in sperm.\",\n      \"method\": \"Genetic epistasis: crossbreeding Sec46Ala-Gpx4+/- mice with Alox15-/- mice, sperm motility analysis, fertility assessment, structural EM\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous genetic epistasis with functional rescue in vivo\",\n      \"pmids\": [\"27634046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Alox15 (15-lipoxygenase) in sperm cytoplasmic droplets is required for normal epididymal sperm maturation and cytoplasmic droplet migration; Alox15-null males retain cytoplasmic droplets with intact mitochondria, unlike wild-type where droplets contain only hollow membrane vesicles.\",\n      \"method\": \"Differential interference contrast microscopy, transmission electron microscopy of Alox15-knockout vs. wild-type sperm\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined ultrastructural and functional phenotype\",\n      \"pmids\": [\"20449608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ALOX15 disruption in hyperlipidemic ApoE-/- mice reduces hepatic steatosis, inflammation, and insulin resistance; absence of Alox15 upregulates insulin receptor substrate-2, exerts opposing effects on JNK and AMPK phosphorylation, and protects hepatocytes from TNFα-induced apoptosis.\",\n      \"method\": \"Double-knockout mouse model (ApoE-/-/Alox15-/-), gene expression, phosphorylation assays, isolated hepatocyte apoptosis assay\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double-KO with molecular pathway analysis and ex vivo validation\",\n      \"pmids\": [\"20967760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Vagus nerve stimulation (VNS) promotes resolution of inflammation in zymosan-induced peritonitis by increasing specialized proresolving mediators (SPMs) from the DHA and DPA metabolomes; this effect is abolished in Alox15-deficient mice, placing Alox15 as a required mediator of VNS-driven SPM biosynthesis.\",\n      \"method\": \"Electrical VNS in Alox15-knockout mice, lipid mediator metabololipidomics, peritonitis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (KO) combined with lipidomics in well-controlled in vivo model\",\n      \"pmids\": [\"35622894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The anti-colitis protective effect of elevated n-3 PUFA tissue status in fat1 transgenic mice requires Alox15; Alox15 deficiency counteracts protection by suppressing 15-HEPE formation, and intraperitoneal 15S-HEPE treatment alone protects wild-type mice from colitis.\",\n      \"method\": \"Fat1 transgenic × Alox15-/- crossbreeding, DSS and TNBS colitis models, lipid mediator analysis, 15-HEPE administration\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with product rescue experiment\",\n      \"pmids\": [\"33710695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Female Alox15-/- mice are protected from DSS-induced colitis; mechanistically, the major Alox15 product in mice (12S-HETE) enantioselectively compromises transepithelial electric resistance and reduces ZO-1 tight junction protein expression in colon epithelial cells, while human ALOX15 transgenic overexpression intensifies colitis.\",\n      \"method\": \"Alox15 KO mice, DSS colitis model, in vitro transepithelial resistance assay with exogenous 12S-HETE, ZO-1 expression analysis, transgenic overexpression\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO, transgenic OE, and in vitro mechanistic assay with defined lipid mediator\",\n      \"pmids\": [\"29702245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"12/15-LO (Alox15) is expressed in macrophages but not B or T cells in NOD mice; Alox15 deletion reduces proinflammatory cytokine expression in macrophages and prevents diabetes transfer by splenocytes, while also maintaining islet transcription factor expression and beta cell mass.\",\n      \"method\": \"qRT-PCR of immune cell subsets, NOD-Alox15null mouse, adoptive transfer assay, beta cell mass measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with adoptive transfer epistasis, cell-type-specific expression defined\",\n      \"pmids\": [\"23437231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALOX15 upregulation in the liver produces 13-HODE from linoleic acid, which induces oxidative stress, ER stress, and apoptosis in hepatocytes; ALOX15 knockout prevents alcohol-induced liver damage, and linoleic acid (not ethanol or acetaldehyde) induces ALOX15 expression in hepatocytes.\",\n      \"method\": \"ALOX15 knockout mice, pharmacologic inhibitor (PD146176), hepatocyte culture with 13-HODE, ALOX15 induction assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse, pharmacologic inhibition, and in vitro mechanistic dissection\",\n      \"pmids\": [\"28827690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Efferocytosis potentiates ALOX15 expression in alternatively activated human macrophages via LXR activation: AC uptake upregulates LXR-dependent gene expression (suppressed by NPC1 inhibition), and LXR/IL-13 co-stimulation enhances ALOX15 expression and increases SPM precursor (15-HETE, 17-HDHA, resolvin D5) synthesis; LXRα/β silencing attenuates this potentiation.\",\n      \"method\": \"Primary human macrophage efferocytosis assay, LXR agonist treatment, NPC1 inhibition, LXRα/β siRNA silencing, global transcriptome analysis, LC-MS/MS lipid mediator quantification\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — primary human macrophages, RNAi, pharmacologic tools, and lipidomics with multiple orthogonal approaches\",\n      \"pmids\": [\"33177619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A coding SNP in ALOX15 (T560M) results in a ~20-fold reduction in catalytic activity in vitro, creating a near-null variant of human 12/15-LOX.\",\n      \"method\": \"ALOX15 resequencing, in vitro catalytic activity assay of 560M vs. 560T variants\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic characterization of the variant\",\n      \"pmids\": [\"17959182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Alox15 in the prefrontal cortex metabolizes DHA to 17S-hydroxy-DHA, which is converted to resolvin D1; inhibition or antisense knockdown of Alox15 in the prefrontal cortex reduces resolvin D1 levels, blocks hippocampo-prefrontal cortical LTP, and impairs spatial working memory.\",\n      \"method\": \"RT-PCR, Western blot, immunohistochemistry, immuno-electron microscopy, LC-MS quantification, Alox15 inhibition/antisense knockdown in vivo, T-maze and LTP assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — localization with functional consequence, loss-of-function with defined biochemical and behavioral readouts\",\n      \"pmids\": [\"28181190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hypoxic cardiac fibroblasts from failing hearts increase ALOX15 expression and produce 15-HETE; conditioned medium from these fibroblasts decreases beating frequency of human iPSC-derived cardiomyocytes in an ALOX15-dependent manner.\",\n      \"method\": \"Cardiac fibroblast isolation, hypoxic culture, gene expression, 15-HETE measurement, conditioned medium transfer to iPS-cardiomyocytes, calcium imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional paracrine assay with ALOX15-dependency, single lab\",\n      \"pmids\": [\"30138423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Alox15 expression in mouse prefrontal cortex is regulated epigenetically by histone acetylation; HDAC inhibitors (trichostatin A, sodium butyrate) and class I-specific HDAC inhibitors upregulate Alox15, while the p300 HAT inhibitor C646 modulates this upregulation, implicating p300 HAT in differentiation-associated Alox15 upregulation in neurons.\",\n      \"method\": \"HDAC inhibitor treatment of SH-SY5Y cells, p300 HAT inhibitor co-treatment, retinoic acid differentiation, mRNA expression analysis, primary cortical neuron development time-course\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacologic manipulation with expression readout, no direct ChIP or mechanistic confirmation of p300 binding to Alox15 locus\",\n      \"pmids\": [\"29235036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"15-LOX-1 overexpression in HCT-116 colon cancer cells induces ERK1/2 phosphorylation, decreases p21(Cip/WAF1) expression, and increases cell growth; the LOX inhibitor NDGA reverses these effects, identifying 13-S-HODE as the active metabolite mediating MEK-ERK1/2 signaling.\",\n      \"method\": \"15-LOX-1 transfection, ERK1/2 phosphorylation assay, p21 expression analysis, LOX inhibitor (NDGA) treatment, sodium butyrate/13-S-HODE treatment\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression with defined signaling readout, pharmacologic dissection; single lab\",\n      \"pmids\": [\"15165036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Selenoprotein P (SelP) exhibits in vitro lipid hydroperoxidase activity against 15-HpETE produced by ALOX15, attenuating 15-HpETE oxidation in cellular assays and in a transcellular model where ALOX15 is metabolically active, establishing SelP as an extracellular antioxidant defense against ALOX15 products.\",\n      \"method\": \"In vitro hydroperoxidase assay, cellular 15-HpETE oxidation assay, transcellular assay with metabolically active 15-LOX-1\",\n      \"journal\": \"Prostaglandins, leukotrienes, and essential fatty acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay confirmed in cellular context; modest activity noted\",\n      \"pmids\": [\"20826080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SSAT1 activation upregulates ALOX15 expression in primary cortical neurons; SSAT1 knockdown downregulates ALOX15 and reduces ferroptosis (lipid hydroperoxide production, viability loss) in neurons treated with oxidative stress; SSAT1 overexpression decreases GPX4 and SLC7A11 expression; ALOX15 inhibitor PD146176 partially reverses SSAT1-induced ferroptosis, placing ALOX15 downstream of SSAT1 in neuronal ferroptosis.\",\n      \"method\": \"SSAT1 siRNA/overexpression in primary neurons, ALOX15 inhibitor treatment, viability assay, lipid hydroperoxide measurement, GPX4/SLC7A11 expression analysis, rat I/R model\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi epistasis and pharmacologic inhibition with defined molecular readouts; single lab\",\n      \"pmids\": [\"35090880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DHODH inhibits the P53/ALOX15 signaling pathway in neurons to reduce ferroptosis after spinal cord injury; DHODH decreases P53 expression, which in turn suppresses ALOX15 expression and reduces lipid peroxide production and mitochondrial damage.\",\n      \"method\": \"Rat SCI model, erastin-induced PC12 cells, molecular and histological ferroptosis assessment, DHODH modulation, P53/ALOX15 pathway analysis\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro models with pathway analysis; pathway placement by epistasis\",\n      \"pmids\": [\"36942513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGF21 deficiency leads to abnormal activation of the ALOX15/15-HETE pathway, triggering innate immunity-dominated pro-inflammatory responses in liver grafts during ischemia/reperfusion injury; pharmacological FGF21 administration suppresses this pathway and protects against hepatic I/R injury.\",\n      \"method\": \"Male mouse models of hepatic I/R injury and orthotopic LT, FGF21-deficient mice, arachidonic acid metabolomics, pharmacologic FGF21 administration\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic deficiency model with metabolomic pathway validation and pharmacologic rescue; single lab\",\n      \"pmids\": [\"39362839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAFB transcription factor in macrophages directly regulates ALOX15 expression during ischemic acute kidney injury; macrophage-specific Mafb deficiency significantly decreases Alox15 mRNA and protein in infiltrating macrophages; in vitro, MAFB regulates Alox15 expression under the COX-2/PGE2/EP4 pathway, mediating a lipid mediator class switch from pro-inflammatory to proresolving mediators.\",\n      \"method\": \"Macrophage-specific Mafb-KO mice, ischemia-reperfusion AKI model, mRNA/protein analysis, in vitro PGE2/EP4 pathway assay, lipid mediator profiling\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — macrophage-specific KO with in vitro mechanistic confirmation; single lab\",\n      \"pmids\": [\"39230290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALOX15 forms a complex with PEBP1 (phosphatidylethanolamine-binding protein 1) in macrophages under psychological stress, mediating membrane phospholipid peroxidation; disruption of this ALOX15/PEBP1 interaction (by DZXY components) inhibits phospholipid peroxidation and restores macrophage phagocytic capacity. Confirmed by co-immunoprecipitation and microscale thermophoresis.\",\n      \"method\": \"LC-MS/MS phospholipidomics, co-immunoprecipitation, microscale thermophoresis (MST), molecular docking, activity verification, flow cytometry\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and MST biophysical binding confirmed; functional consequences validated in vivo and in vitro\",\n      \"pmids\": [\"38492368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conformational heterogeneity of rabbit ALOX15 and human ALOX15B: native PAGE shows two conformers with distinct electrophoretic mobilities; MD simulations indicate substrate-bound geometry at the active site affects dimer interface geometry; Gln596 mutations impair allosteric properties as shown by kinetics and MD.\",\n      \"method\": \"Native PAGE, site-directed mutagenesis, MD simulations, in silico docking, kinetic measurements\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — structural and kinetic analysis with mutagenesis; single lab\",\n      \"pmids\": [\"33807076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Gln596 in mammalian ALOX15 does not directly interact with the carboxylate of arachidonic acid; instead, mutations at Gln596 destabilize ALOX15 secondary and tertiary structure by disrupting local electrostatic interactions, and impair allosteric properties by altering dimer interface geometry.\",\n      \"method\": \"Site-directed mutagenesis, in silico substrate docking, molecular dynamics simulations, enzyme kinetics, structural assays of rabbit and human ALOX15\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with structural and kinetic readouts; computational validation; single lab\",\n      \"pmids\": [\"32151768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"N-substituted 5-(1H-indol-2-yl)-2-methoxyaniline derivatives are allosteric inhibitors that selectively inhibit the linoleate oxygenase activity of rabbit and human ALOX15 without affecting arachidonic acid oxygenation; MD simulations using a dimer model suggest inhibitor binding at one monomer active site induces conformational changes in the other monomer impairing productive linoleic acid complex formation.\",\n      \"method\": \"Synthesis of inhibitor series, steady-state enzyme kinetics, mutagenesis studies, molecular dynamics simulations of ALOX15 dimer\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinetics, mutagenesis, and MD simulations defining allosteric mechanism; single lab\",\n      \"pmids\": [\"35073698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mutagenesis of Val418 and Val419 sequence determinants in porcine ALOX15 (arachidonic acid 12-lipoxygenating) converts it to a dominantly 15-lipoxygenating enzyme; QM/MM calculations show that the Val418Ile+Val419Met double mutant lowers the energy barrier for 15-lipoxygenation relative to 12-lipoxygenation, altering the catalytic mechanism of initial hydrogen abstraction.\",\n      \"method\": \"Site-directed mutagenesis, docking and MD simulations, QM/MM calculations, in vitro enzymatic assay\",\n      \"journal\": \"Chemistry (Weinheim)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with QM/MM mechanistic characterization of hydrogen abstraction\",\n      \"pmids\": [\"29154477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Induction of Alox15 in the intestine of iron-deficient rats leads to production of biologically active lipid molecules (12-HETE, 13-HODE, 13-HOTE) as shown by HPLC analysis, perturbing intestinal lipid homeostasis.\",\n      \"method\": \"Gene chip studies, TaqMan RT-PCR, polyclonal antibody protein detection, HPLC lipid analysis in iron-deficient rats and Belgrade rats\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent iron-deficiency models with protein and product confirmation; single lab\",\n      \"pmids\": [\"18258795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ALOX15 expression in colon cancer cells suppresses HIF-1α protein expression and stability under hypoxia, inhibiting VEGF expression, angiogenesis, and cancer cell migration and invasion.\",\n      \"method\": \"15-LOX-1 reexpression in multiple colon cancer cell lines (HCT116, HT29LMM, LoVo), HIF-1α stability assay, VEGF measurement, migration/invasion assay, angiogenesis assay\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function in multiple cell lines with defined molecular and functional readouts; single lab\",\n      \"pmids\": [\"24634093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Macrophage-derived exosomes containing miRNA-660-5p are transported into cervical cancer cells where miRNA-660-5p attenuates ALOX15 expression to suppress ferroptosis; upregulation of miRNA-660-5p in macrophages is driven by autocrine IL-4/IL-13-activated STAT6 pathway.\",\n      \"method\": \"Exosome isolation and transfer, miRNA-660-5p overexpression/knockdown, ALOX15 expression analysis, ferroptosis assays, STAT6 pathway inhibition, in vivo tumor models\",\n      \"journal\": \"Acta pharmaceutica Sinica B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — exosome transfer with miRNA mechanism and STAT6 pathway placement; in vivo validation\",\n      \"pmids\": [\"37425043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALOX15 aggravates MASLD/steatotic liver disease via the PPARγ/CD36 axis: ALOX15 overexpression increases fatty acid uptake and triglyceride accumulation; PPARγ antagonist GW9662 or CD36 inhibitor blocks ALOX15-mediated lipid accumulation; liraglutide (GLP-1RA) improves hepatic lipid accumulation by suppressing the ALOX15/PPARγ/CD36 pathway.\",\n      \"method\": \"ALOX15 lentiviral overexpression and siRNA knockdown in HepG2 cells, transcriptomics, metabolomics, pharmacologic inhibition of PPARγ/CD36, HFD/STZ mouse model\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression and KD with pathway pharmacologic validation in vitro and in vivo; single lab\",\n      \"pmids\": [\"39815992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bmal1 in AML cells recruits EZH2 to the EBF3 promoter, enhancing its methylation and suppressing EBF3 expression; EBF3 binds the ALOX15 promoter to enhance ALOX15 expression, promoting ferroptosis; Bmal1 therefore suppresses ALOX15-mediated ferroptosis via EZH2/EBF3 axis.\",\n      \"method\": \"ChIP for EZH2 at EBF3 promoter, EBF3 ChIP at ALOX15 promoter, Bmal1 overexpression/knockdown, EBF3 knockdown, ferroptosis assays, xenograft model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for upstream regulatory events and ferroptosis readout in vivo; single lab\",\n      \"pmids\": [\"37271497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PER1 binds the SREBF2 promoter to repress SREBF2 transcription; SREBF2 in turn binds the ALOX15 promoter to repress ALOX15 transcription; thus PER1 promotes ALOX15-mediated ferroptosis in granulosa cells in PCOS by removing SREBF2-mediated repression of ALOX15.\",\n      \"method\": \"ChIP-qPCR, promoter binding assays, PER1 overexpression, SREBF2 overexpression/knockdown, ALOX15 silencing, ferroptosis assays in granulosa cells\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for transcription factor binding at ALOX15 promoter, epistasis experiment; single lab\",\n      \"pmids\": [\"38653359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHI (dihydrotanshinone I) upregulates EGR1, leading to decreased DNMT1 expression, increased ALOX15 demethylation, and ALOX15-dependent ferroptosis induction in hepatic stellate cells; EGR1 is a direct pharmacological target of DHI confirmed by molecular docking.\",\n      \"method\": \"Transcriptome sequencing, qRT-PCR, Western blot, DNMT1 overexpression, ALOX15 siRNA, methylation analysis, molecular docking\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic mechanism with transcriptomics and functional validation; single lab\",\n      \"pmids\": [\"39675198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lachnospiraceae-derived pyruvate inhibits ALOX15 expression and reduces ferroptosis in donor livers during transplantation I/R injury; reduced nuclear translocation of Foxo3 further suppresses ALOX15 expression, identifying a Foxo3-Alox15 axis.\",\n      \"method\": \"Multi-omics, Lachnospiraceae treatment in rat LT models, Foxo3 nuclear translocation analysis, Alox15 expression measurement, ferroptosis assays\",\n      \"journal\": \"Gut microbes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with mechanistic pathway validation in vivo; single lab\",\n      \"pmids\": [\"39882747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Spinal microglial ALOX15 (15-LOX-1) mediates TLR4-dependent hepoxilin production and tactile allodynia; intrathecal TLR4 activation increases 15-LOX-1 expression in primary spinal microglia (but not astrocytes) and hepoxilin production; selective 15-LOX-1 inhibitors (ML127, ML351) reduce activity of rat 15-LOX-1 expressed in HEK-293T cells and completely abrogate TLR4-induced allodynia.\",\n      \"method\": \"Intrathecal KLA administration, primary spinal microglia/astrocyte culture, selective antibody targeting, HEK-293T heterologous expression with inhibitor assay, in vivo pharmacology\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic inhibition, cell-type-specific expression, and in vivo pharmacologic rescue with selective inhibitors\",\n      \"pmids\": [\"30130298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF1A, whose transcription is enhanced by lactate-driven histone lactylation at its promoter, activates the ACSL4/LPCAT3/ALOX15 pathway to induce ferroptosis in severe acute pancreatitis; sh-HIF1A reduces ALOX15 expression and ferroptosis markers; ChIP-qPCR confirms HIF1A promoter binding.\",\n      \"method\": \"sh-HIF1A mice, SAP mouse model, ChIP-qPCR, luciferase reporter, Western blot, qPCR, ferroptosis marker measurement\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD and ChIP for HIF1A at ALOX15 pathway; pathway placement by epistasis; single lab\",\n      \"pmids\": [\"39676583\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALOX15 is a lipid-peroxidizing enzyme that oxygenates polyunsaturated fatty acids (arachidonic acid, linoleic acid, DHA, EPA) to generate bioactive hydroperoxy lipids (15-HpETE, 13-HODE, 12-HETE, 15-HEPE, resolvins, lipoxins); its reaction specificity (12- vs. 15-lipoxygenating) is determined by conserved triad residues and evolved in higher primates toward 15-lipoxygenation to optimize lipoxin and SPM biosynthesis; in ferroptosis, ALOX15 directly peroxidizes PUFA-phospholipids (acting downstream of p53/SAT1 and upstream of GPX4/PGC1α degradation pathways); it is transcriptionally regulated by SPI1, NuRD/HDAC complexes, GATA-6, MAFB, and epigenetic histone acetylation; it forms a functional complex with PEBP1 to redirect peroxidase activity toward membrane phospholipids; it suppresses Wnt/β-catenin signaling via PI3P peroxidation to inhibit LRP5 recycling; and it plays defined roles in erythropoiesis, sperm maturation, inflammation resolution, bone density, hepatic lipid metabolism, and neuropathic pain through cell-type-specific production of lipid mediators.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ALOX15 is a non-heme iron dioxygenase that oxygenates polyunsaturated fatty acids—both free and esterified in membrane phospholipids—to generate bioactive lipid mediators including 15-HpETE, 13-HODE, 12-HETE, 15-HEPE, and resolvin D1, with positional specificity (12- vs. 15-lipoxygenation) governed by conserved triad residues that evolved in higher primates to optimize 15-lipoxygenation and lipoxin synthase activity [PMID:27412860, PMID:25731857, PMID:29154477]. Through these lipid products, ALOX15 drives ferroptotic cell death by peroxidizing PUFA-phosphatidylethanolamines—acting downstream of p53/SSAT1 and upstream of GPX4—and forms a complex with PEBP1 to redirect peroxidase activity toward membrane phospholipids; its metabolite 15-HpETE also promotes PGC1α ubiquitin-dependent degradation via RNF34 to attenuate mitochondrial biogenesis [PMID:35970840, PMID:36987924, PMID:35090880, PMID:38492368]. ALOX15 mediates inflammation resolution by serving as the required biosynthetic enzyme for specialized proresolving mediators (SPMs) from DHA and EPA in macrophages, a function potentiated by efferocytosis-driven LXR activation and regulated by transcription factors including SPI1, MAFB, NuRD/HDAC complexes, and GATA-6 [PMID:35622894, PMID:33710695, PMID:33177619, PMID:16320347, PMID:19198625, PMID:39230290]. In addition, ALOX15 suppresses Wnt/β-catenin signaling by peroxidizing PI3P to impair LRP5 endosomal recycling, regulates peak bone density as a negative regulator, is required for normal sperm cytoplasmic droplet remodeling, and contributes to hepatic lipid metabolism and neuropathic pain through cell-type-specific lipid mediator production [PMID:32814052, PMID:14716014, PMID:20449608, PMID:20967760, PMID:30130298].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing ALOX15 as the principal linoleic acid oxygenase in colon cells resolved the question of which enzyme generates the pro-apoptotic mediator 13-S-HODE downstream of NSAIDs, linking ALOX15 catalytic activity directly to apoptosis induction.\",\n      \"evidence\": \"Enzymatic activity assays, pharmacologic inhibition with caffeic acid, and rescue with exogenous 13-S-HODE in colorectal cancer cell lines\",\n      \"pmids\": [\"10904086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream transcriptional mechanism by which NSAIDs induce ALOX15 was not defined\", \"Whether 13-S-HODE acts through a specific receptor was not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that Alox15 knockout improves bone mineral density in mice established ALOX15 as a negative regulator of bone formation, revealing an unexpected physiological role beyond classical eicosanoid biology.\",\n      \"evidence\": \"Alox15 KO mouse crosses and pharmacologic inhibitor treatment with bone density and strength measurements\",\n      \"pmids\": [\"14716014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific lipid mediator and downstream pathway by which ALOX15 suppresses osteoblast activity was not identified\", \"Human genetic validation was lacking\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of SPI1 binding to a promoter polymorphism and NuRD/HDAC-mediated repression at the ALOX15 promoter established the first transcriptional regulatory mechanisms controlling cell-type-specific ALOX15 expression.\",\n      \"evidence\": \"EMSA, reporter assays with mutagenesis in macrophages (SPI1); ChIP, siRNA knockdown, and HDAC inhibitor treatment in colon cancer cells (NuRD)\",\n      \"pmids\": [\"16320347\", \"19198625\", \"17167069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SPI1 and NuRD regulatory circuits integrate in immune cells was not addressed\", \"GATA-6 contribution required combination treatment, suggesting it is a co-factor rather than primary regulator\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Characterization of the T560M near-null coding variant provided the first human genetic evidence that ALOX15 catalytic activity varies substantially in the population, with implications for disease susceptibility studies.\",\n      \"evidence\": \"Resequencing and in vitro catalytic activity assay of T560M vs. wild-type ALOX15\",\n      \"pmids\": [\"17959182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Population frequency and clinical phenotypic consequences of T560M were not established\", \"No structural explanation for the ~20-fold activity reduction was provided\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that Alox15 is required for sperm cytoplasmic droplet remodeling and organelle clearance during epididymal maturation revealed a specialized developmental function in male germ cells, later confirmed by genetic epistasis with Gpx4.\",\n      \"evidence\": \"Alox15-KO sperm ultrastructural analysis by TEM; genetic epistasis with Gpx4 Sec46Ala heterozygotes restoring sperm motility and fertility\",\n      \"pmids\": [\"20449608\", \"27634046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific ALOX15-derived lipid mediator driving organelle clearance in sperm was not identified\", \"Whether this function is conserved in human spermatogenesis is unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Double-KO studies showed Alox15 disruption protects against hepatic steatosis and insulin resistance in hyperlipidemic mice, establishing ALOX15 as a driver of hepatic lipid pathology through JNK/AMPK and IRS-2 modulation.\",\n      \"evidence\": \"ApoE−/−/Alox15−/− double-knockout mouse, phosphorylation assays, hepatocyte apoptosis assay\",\n      \"pmids\": [\"20967760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct ALOX15 lipid mediator responsible for hepatic signaling was not fully defined\", \"Applicability to non-hyperlipidemic hepatic disease was untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis showed that Alox15 deletion does not rescue Gpx4 catalytic-null embryonic lethality, establishing that ALOX15 is not the sole oxidative driver of Gpx4-dependent developmental lethality despite its role in ferroptosis.\",\n      \"evidence\": \"Crossbreeding of Gpx4 Sec46Ala knock-in with Alox15-KO mice, embryonic viability assessment\",\n      \"pmids\": [\"25313597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which other lipoxygenases or non-enzymatic pathways compensate in the Gpx4-null embryonic context was not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Systematic mutagenesis of triad determinants (Leu353, Ile593) and Val418/Val419 across species orthologs, combined with QM/MM calculations, resolved the structural basis of 12- vs. 15-lipoxygenation specificity and demonstrated that ALOX15 evolved 15-lipoxygenating capability in higher primates to optimize lipoxin synthase activity.\",\n      \"evidence\": \"Recombinant mutagenesis, in vitro enzymatic assays across multiple orthologs, QM/MM calculations of hydrogen abstraction energy barriers\",\n      \"pmids\": [\"25731857\", \"27412860\", \"29154477\", \"28400162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structures of substrate-bound human ALOX15 confirming the QM/MM predictions are lacking\", \"How positional specificity changes affect in vivo SPM profiles in primates was not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localization and functional studies in prefrontal cortex established that ALOX15 converts DHA to 17S-HDHA/resolvin D1 in neurons, directly linking ALOX15 to synaptic plasticity (LTP) and spatial working memory.\",\n      \"evidence\": \"RT-PCR, immuno-EM localization, LC-MS quantification, in vivo Alox15 inhibition/antisense knockdown with T-maze and LTP electrophysiology\",\n      \"pmids\": [\"28181190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor through which resolvin D1 modulates LTP was not identified\", \"Whether neuronal ALOX15 is relevant to human cognitive function is untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that spinal microglial ALOX15 mediates TLR4-dependent hepoxilin production and tactile allodynia identified a cell-type-specific pro-nociceptive role, with selective ALOX15 inhibitors (ML127, ML351) fully abrogating pain behavior.\",\n      \"evidence\": \"Primary spinal microglia culture, HEK-293T heterologous expression with selective inhibitors, intrathecal TLR4 activation model\",\n      \"pmids\": [\"30130298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ALOX15-dependent allodynia operates in chronic pain conditions beyond TLR4 activation was not explored\", \"The hepoxilin receptor mediating nociception was not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterization of ALOX15 products (12S-HETE) compromising tight junction integrity (ZO-1) in colon epithelium, combined with KO protection from colitis, established a mechanism by which ALOX15 promotes intestinal barrier dysfunction.\",\n      \"evidence\": \"Alox15-KO and human ALOX15 transgenic mice in DSS colitis model, transepithelial resistance assay with enantioselective 12S-HETE\",\n      \"pmids\": [\"29702245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor or signaling pathway through which 12S-HETE reduces ZO-1 was not defined\", \"Whether the protective vs. pro-resolving roles of ALOX15 in colitis are sex-dependent was not fully explored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that ALOX15 peroxidizes PI3P to generate PI3P-13-HODE, which disrupts SNX17-LRP5 binding, inhibits LRP5 recycling, and suppresses Wnt/β-catenin signaling, revealed a novel non-classical mechanism linking lipid peroxidation to endosomal sorting and tumor suppression.\",\n      \"evidence\": \"ALOX15 transgenic mouse intestine, APC-mutant model, PI3P-lipid binding assays, endosome tracking\",\n      \"pmids\": [\"32814052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PI3P peroxidation affects other PI3P-dependent endosomal cargo is unknown\", \"Structural basis for loss of SNX17 binding to oxidized PI3P was not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Efferocytosis was shown to potentiate ALOX15 expression in human macrophages through LXR activation, linking phagocytic clearance of apoptotic cells to amplified SPM biosynthesis and establishing a feedforward resolution circuit.\",\n      \"evidence\": \"Primary human macrophage efferocytosis assay, LXR agonist and NPC1 inhibition, LXRα/β siRNA, LC-MS/MS lipid mediator profiling\",\n      \"pmids\": [\"33177619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LXR directly binds the ALOX15 promoter or acts indirectly was not resolved\", \"The contribution of other LXR target genes to SPM amplification was not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic epistasis confirmed that the anti-colitis effect of elevated tissue n-3 PUFAs requires Alox15, with 15S-HEPE identified as a sufficient protective mediator, resolving the question of which enzyme converts dietary omega-3 fatty acids into bioactive anti-inflammatory products in vivo.\",\n      \"evidence\": \"Fat1 transgenic × Alox15-KO crossbreeding, DSS/TNBS colitis models, lipid mediator analysis, 15-HEPE rescue\",\n      \"pmids\": [\"33710695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor and signaling pathway through which 15S-HEPE protects from colitis was not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multi-omics and chemogenetic studies established ALOX15 as the primary initiator of PUFA-phospholipid peroxidation (specifically PE-PUFAs) in cardiomyocytes during ischemia-reperfusion, positioning it as a 'burning point' for ferroptotic signaling.\",\n      \"evidence\": \"Multi-omics with chemogenetic approaches in animal and cellular models of cardiac I/R\",\n      \"pmids\": [\"35970840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ALOX15 is activated or stabilized specifically during ischemia-reperfusion was not mechanistically defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ALOX15 was placed as a required mediator of vagus nerve stimulation-driven SPM biosynthesis, establishing the neuro-immune mechanism by which cholinergic anti-inflammatory signaling resolves inflammation through ALOX15-dependent lipid mediator production.\",\n      \"evidence\": \"Electrical VNS in Alox15-KO mice, lipid mediator metabololipidomics in zymosan peritonitis model\",\n      \"pmids\": [\"35622894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cell type mediating VNS-dependent ALOX15 activation was not identified\", \"Whether VNS directly upregulates ALOX15 or increases substrate availability was not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification that 15-HpETE promotes PGC1α binding to the E3 ligase RNF34, leading to PGC1α ubiquitin-dependent degradation and attenuated mitochondrial biogenesis, revealed a mechanistic link between ALOX15 catalytic products and mitochondrial dysfunction in ferroptotic cardiomyocytes.\",\n      \"evidence\": \"Myocardial-specific ALOX15 KO mice, co-IP of PGC1α-RNF34, metabolomics, pharmacologic inhibition with ML351\",\n      \"pmids\": [\"36987924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 15-HpETE acts directly on PGC1α or RNF34 to promote their interaction is not structurally resolved\", \"Generalizability of this mechanism to non-cardiac ferroptosis contexts is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MAFB was identified as a direct transcriptional regulator of ALOX15 in macrophages during ischemic AKI, operating downstream of the COX-2/PGE2/EP4 pathway to mediate a lipid mediator class switch from pro-inflammatory to proresolving, answering how macrophage phenotype transitions engage ALOX15 transcription.\",\n      \"evidence\": \"Macrophage-specific Mafb-KO mice, AKI model, in vitro PGE2/EP4 pathway assay, lipid mediator profiling\",\n      \"pmids\": [\"39230290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAFB binds the ALOX15 promoter directly was not confirmed by ChIP\", \"Generalizability beyond renal I/R macrophages is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Co-immunoprecipitation and microscale thermophoresis confirmed that ALOX15 forms a functional complex with PEBP1 in macrophages, redirecting its peroxidase activity toward membrane phospholipids; disruption of this complex inhibits phospholipid peroxidation and ferroptosis.\",\n      \"evidence\": \"Co-IP, MST biophysical binding, LC-MS/MS phospholipidomics, molecular docking, in vivo and in vitro functional verification\",\n      \"pmids\": [\"38492368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the ALOX15-PEBP1 interface in the context of membrane substrates is not resolved\", \"Independent replication in a second laboratory is needed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the crystal structure of substrate-bound human ALOX15, the identity of receptors for many ALOX15-derived lipid mediators (hepoxilins, 15-HEPE, 13-S-HODE), the mechanism by which ALOX15 is selectively activated during ischemia, and how the pro-inflammatory versus pro-resolving functions of ALOX15 are spatiotemporally segregated within the same cell type.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No substrate-bound crystal structure of human ALOX15 exists\", \"Receptors for many ALOX15 products remain unidentified\", \"Spatiotemporal regulation of pro- vs. anti-inflammatory ALOX15 activity in single cells is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [2, 4, 5, 6, 7, 35]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13, 31]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 31]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 4, 5, 6, 7, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 27, 28, 40, 41]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 16, 18, 20, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 25]}\n    ],\n    \"complexes\": [\n      \"ALOX15-PEBP1 complex\"\n    ],\n    \"partners\": [\n      \"PEBP1\",\n      \"GPX4\",\n      \"RNF34\",\n      \"SPI1\",\n      \"MTA1\",\n      \"HDAC1\",\n      \"MAFB\",\n      \"LRP5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}