Affinage

ALOX15B

Polyunsaturated fatty acid lipoxygenase ALOX15B · UniProt O15296

Length
676 aa
Mass
75.9 kDa
Annotated
2026-04-28
22 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALOX15B is a non-heme iron-containing lipoxygenase that oxygenates arachidonic acid and other polyunsaturated fatty acids at the C-15 position to generate 15S-HpETE/15S-HETE, with product specificity determined by active-site residues Asp602/Val603 (PMID:10393855, PMID:37373195). The enzyme translocates to the plasma membrane upon Ca²⁺ stimulation via a membrane insertion loop and can oxygenate phospholipid-esterified substrates within bilayers; its membrane retention depends on S-palmitoylation, which is removed by ABHD17C downstream of KRAS/ERK1 signaling, targeting ALOX15B for CUL4/DDB1/DCAF10-mediated proteasomal degradation (PMID:27435673, PMID:40569151). ALOX15B-derived lipid peroxides activate ERK1/2 to sustain SREBP2-dependent cholesterol biosynthesis in macrophages, promote PASMC proliferation via ERK/p38 MAPK, modulate keratinocyte inflammation through EGFR/JAK1/STAT1, and induce ferroptosis in cancer cells through p53/SLC7A11-dependent and IRF1-driven mechanisms (PMID:38581859, PMID:22018966, PMID:39843435, PMID:36801644, PMID:40749811). In vivo, the balance between 15- and 8-hydroperoxide products determines divergent pro- and anti-inflammatory outcomes, as demonstrated by knock-in mice with humanized product specificity (PMID:37446212, PMID:35740398).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 High

    Establishing that ALOX15B is a 15S-HETE-producing lipoxygenase resolved the identity and dominant product of this second human 15-lipoxygenase isoform.

    Evidence Radiolabeled arachidonic acid incubation with benign prostate tissue, HPLC product identification

    PMID:10393855

    Open questions at the time
    • Catalytic mechanism and active-site determinants of positional specificity unknown
    • Subcellular localization dynamics not addressed
    • No structural information available
  2. 2011 Medium

    Linking the ALOX15B product 15(S)-HETE to PASMC proliferation via MEK/ERK1/2 placed the enzyme's lipid products within a defined mitogenic signaling cascade relevant to pulmonary vascular remodeling.

    Evidence BrdU incorporation, Western blot for p-ERK1/2, MEK inhibitors PD-98059 and U0126 in cultured rabbit PASMCs under hypoxia

    PMID:22018966 PMID:25895668

    Open questions at the time
    • Direct target of 15-HETE upstream of ERK not identified
    • Pathway epistasis relies on pharmacological inhibitors without genetic confirmation in first study
    • Human PASMC data limited
  3. 2016 High

    Demonstrating Ca²⁺-dependent plasma membrane translocation, membrane insertion loop dependency, and oxygenation of phospholipid-esterified substrates in nanodiscs established ALOX15B as a membrane-acting enzyme, not merely a cytosolic lipid oxygenase.

    Evidence Nanodisc reconstitution, site-directed mutagenesis of membrane insertion loop, live-cell imaging in transfected HEK293 cells

    PMID:27435673

    Open questions at the time
    • Structural basis of membrane insertion loop–bilayer interaction unresolved
    • Lipid preferences at the membrane not systematically characterized
  4. 2022 Medium

    Knock-in mice with humanized Alox15b product specificity revealed that the 15- versus 8-HETE product ratio has distinct in vivo physiological consequences including sex-specific hematopoietic and inflammatory phenotypes.

    Evidence Alox15b Tyr603Asp+His604Val knock-in mice, plasma oxylipidomics, hematological analysis, DSS colitis and CFA paw edema models

    PMID:35740398 PMID:37446212

    Open questions at the time
    • Mechanistic targets of 15-HETE vs 8-HETE driving divergent inflammatory outcomes not identified
    • Basis of sex specificity unknown
    • Single lab generated both studies
  5. 2023 High

    Identifying Asp602/Val603 as the determinants of human ALOX15B 15-lipoxygenating specificity resolved the molecular basis for the species-specific product difference between human and mouse orthologs.

    Evidence Reciprocal active-site mutagenesis of recombinant human and mouse enzymes, in vitro assays with multiple PUFA substrates, molecular dynamics

    PMID:37373195

    Open questions at the time
    • No crystal structure of ALOX15B to confirm docking predictions
    • Whether other active-site residues contribute to fine-tuning specificity untested
  6. 2023 Medium

    Placing ALOX15B downstream of p53 and upstream of ferroptosis via the SLC7A11/glutathione axis established a tumor-suppressive lipid peroxidation pathway in bladder cancer.

    Evidence shRNA knockdown, p53 agonist Nutlin-3a, ferrostatin-1 rescue, in vitro and xenograft tumor models

    PMID:36801644

    Open questions at the time
    • Direct lipid peroxidation substrates driving ferroptosis not identified
    • Whether ALOX15B enzymatic activity or protein scaffold is required not dissected
  7. 2024 High

    Demonstrating that ALOX15B-mediated lipid peroxidation activates ERK1/2 to sustain nuclear SREBP2 and cholesterol biosynthesis in macrophages connected the enzyme to sterol metabolism and foam cell biology.

    Evidence siRNA in primary human macrophages, transcriptomics, ERK1/2 inhibition, sterol quantification by mass spectrometry

    PMID:38581859

    Open questions at the time
    • Identity of the specific lipid peroxide species activating ERK1/2 unknown
    • In vivo atherosclerosis relevance not tested
  8. 2025 High

    Discovery that KRAS/ERK1-driven ABHD17C depalmitoylates ALOX15B, triggering CUL4/DDB1/DCAF10-mediated proteasomal degradation, revealed a complete post-translational regulatory circuit controlling ALOX15B stability and ferroptotic capacity in pancreatic cancer.

    Evidence Co-IP, palmitoylation assays, proteasome inhibition, subcellular fractionation, patient-derived organoids, in vivo tumor models

    PMID:40569151

    Open questions at the time
    • Palmitoylation site(s) on ALOX15B not mapped
    • Whether this degradation pathway operates in non-cancer cells unknown
  9. 2025 Medium

    Identifying IRF1 and CEBPA as direct transcriptional activators of ALOX15B and HDAC1/2 as epigenetic repressors defined the transcriptional control layer governing ALOX15B expression across cancer, immune evasion, and bone homeostasis contexts.

    Evidence ChIP-qPCR/ChIP-seq, EMSA, dual-luciferase reporters, HDAC inhibitor treatment, ALOX15B KO mice with OVX

    PMID:40749811 PMID:41527135 PMID:41843143

    Open questions at the time
    • Relative contributions of IRF1, CEBPA, and HDAC1/2 in the same cell type not compared
    • Whether additional transcription factors regulate tissue-specific expression unknown
    • Chromatin architecture at the ALOX15B locus not fully characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the crystal structure of ALOX15B, the identity of specific lipid peroxide species that activate ERK1/2, the palmitoylation site(s), and how the enzyme's dual pro-inflammatory (15-HETE) and context-dependent anti-inflammatory roles are balanced in human disease.
  • No solved 3D structure
  • Direct lipid peroxide mediator of ERK activation not identified
  • S-palmitoylation site(s) not mapped
  • In vivo human genetic evidence linking ALOX15B variants to disease absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-168256 Immune System 1 R-HSA-392499 Metabolism of proteins 1
Partners
ABHD17CCEBPACUL4ADCAF10DDB1HDAC1IRF1SLC7A11

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Human 15-LOX-2 (ALOX15B) catalyzes the oxygenation of arachidonic acid to 15S-HETE as its major product; this activity was demonstrated in benign prostate tissue incubated with [14C]arachidonic acid, with 15-HETE confirmed as the dominant metabolite by HPLC. Radiolabeled substrate incubation with tissue, reverse- and straight-phase HPLC product identification; immunohistochemistry for localization The American journal of pathology High 10393855
2016 Human ALOX15B generates a 15-S-hydroperoxy product from arachidonic acid while murine Alox15b generates an 8-S-product; both enzymes can oxygenate phospholipid-esterified arachidonic acid in a bilayer context (nanodiscs) to a 15-S-product. ALOX15B translocates to the plasma membrane upon Ca2+ ionophore stimulation, and this membrane localization is dependent on a putative membrane insertion loop. In vitro enzyme assays with nanodiscs as membrane mimics; transfected HEK293 cell imaging; site-directed mutagenesis of membrane insertion loop The Journal of biological chemistry High 27435673
2023 The distinct reaction specificities of human ALOX15B (15-hydroperoxy product) versus mouse Alox15b (8-hydroperoxy product) are determined by residues at positions 602-603 (Asp602/Val603 in human; Tyr603/His604 in mouse). Asp602Tyr+Val603His exchange in human ALOX15B murinized its product pattern, while Tyr603Asp+His604Val substitution in mouse Alox15b humanized it; in silico substrate docking supports an inverse substrate binding mechanism. Recombinant protein expression, in vitro enzyme activity assays with multiple polyunsaturated fatty acid substrates, active-site mutagenesis, molecular dynamics simulation and substrate docking International journal of molecular sciences High 37373195
2011 15-LOX-2 product 15(S)-HETE promotes proliferation of pulmonary artery smooth muscle cells (PASMCs) under hypoxia via ERK1/2 (MEK/ERK) phosphorylation; this proliferative effect is blocked by MEK inhibitors PD-98059 and U0126, and by 15-LOX inhibitors NDGA and CDC. Cultured rabbit PASMC proliferation assays, BrdU incorporation, Western blotting for ERK1/2 phosphorylation, pharmacological inhibitors Prostaglandins, leukotrienes, and essential fatty acids Medium 22018966
2015 15-LOX-2/15-HETE signaling promotes pulmonary arterial smooth muscle cell (PASMC) proliferation, cell cycle progression, migration, and suppression of apoptosis under hypoxia through activation of ERK and p38 MAPK phosphorylation. TUNEL assay, flow cytometry, BrdU incorporation, Western blotting for p-ERK and p-p38MAPK in cultured PASMCs and PAH patient/rat lungs Cellular physiology and biochemistry Medium 25895668
2023 p53 activates ALOX15B lipoxygenase activity by suppressing SLC7A11 (cystine transporter), thereby inducing ferroptosis in bladder cancer cells; knockdown of ALOX15B protects bladder cancer cells from p53-induced ferroptosis. shRNA/oe-plasmid transfection, p53 agonist Nutlin-3a treatment, ferroptosis inhibitor ferrostatin-1, iron chelator deferoxamine, in vitro and in vivo tumor models Laboratory investigation Medium 36801644
2024 ALOX15B controls macrophage cholesterol homeostasis through a lipid peroxidation→ERK1/2→SREBP2 axis: ALOX15B-mediated lipid peroxidation activates ERK1/2, which sustains nuclear SREBP2 abundance and activity, thereby regulating cholesterol biosynthetic gene expression and sterol intermediates (desmosterol, lathosterol, 25- and 27-hydroxycholesterol). siRNA silencing of ALOX15B in primary human macrophages, global transcriptome analysis, immunofluorescence, ERK1/2 inhibition, NPC1 inhibition, sterol quantification by mass spectrometry Redox biology High 38581859
2025 ALOX15B silencing in human epidermal keratinocytes augments inflammation by reducing EGFR expression, leading to enhanced JAK1/STAT1 signaling and increased CCL2, CCL5, and CXCL10 secretion; reduced ERK phosphorylation downstream of EGFR also decreases cholesterol biosynthesis gene expression and depletes plasma membrane cholesterol/lipid rafts. siRNA knockdown, lipoxygenase inhibitor ML351, JAK1/STAT1 pathway inhibition, EGFR inhibition, confocal microscopy for membrane lipids, cytokine quantification, skin equivalents Cell death & disease Medium 39843435
2025 In pancreatic cancer, KRAS-mutant/ERK1-driven phosphorylation of ABHD17C promotes depalmitoylation of ALOX15B and its translocation from the plasma membrane to the cytoplasm, leading to proteasome-dependent degradation via the CUL4/DDB1/DCAF10 E3 ligase complex; restoration of S-palmitoylation by methyl protodioscin (which disrupts ABHD17C/ALOX15B interaction) re-localizes ALOX15B to the membrane and induces ferroptosis. Co-IP (ABHD17C–ALOX15B interaction), palmitoylation assays, proteasome inhibition, subcellular fractionation, patient-derived organoids, in vivo tumor models Advanced science High 40569151
2022 In porcine Sertoli cells under heat stress, ALOX15B expression is upregulated and increases 8-HETE and 15-HETE levels, activating the p38-p53 pathway to promote apoptosis; p38 inhibition reduces ALOX15B expression, and p38/p53 feedback regulates ALOX15B and lipid peroxide levels. Metabolomics (LC-MS), siRNA knockdown, ALOX15B inhibitor baicalein, p38 inhibitor, p53 inhibitor, apoptosis assays Theriogenology Medium 35344833
2022 Humanization of mouse Alox15b reaction specificity (Tyr603Asp+His604Val knock-in) in vivo alters the plasma oxylipidome and leads to a gender-specific (male-only) premature growth arrest and impaired red blood cell parameters in aging mice, indicating that ALOX15B product specificity (15- vs 8-HETE) has distinct physiological consequences in the hematopoietic system. Knock-in mouse model, plasma oxylipidomics, hematological parameter measurement, body weight tracking Biomedicines Medium 35740398
2023 Humanization of mouse Alox15b reaction specificity (knock-in Tyr603Asp+His604Val) sensitizes female mice to dextran sodium sulfate-induced colitis (more weight loss, slower recovery) but partially protects in complete Freund's adjuvant-induced paw edema, demonstrating that the 15-hydroperoxy versus 8-hydroperoxy product balance of ALOX15B determines divergent pro- and anti-inflammatory outcomes in distinct disease contexts. Knock-in mouse models, DSS colitis model, CFA paw edema model, eicosanoid profiling, pain perception tests International journal of molecular sciences Medium 37446212
2013 Non-synonymous polymorphic variants of ALOX15B (p.Arg486His, p.Gln656Arg, p.Ile676Val) show similar enzyme activity and Michaelis-Menten kinetics to wild-type ALOX15B when expressed and assayed in vitro, indicating these common variants do not alter catalytic function. Recombinant protein expression, in vitro enzyme activity assays, Michaelis-Menten kinetics Clinical biochemistry Medium 24373925
2025 IRF1 directly transcriptionally activates ALOX15B by binding its promoter, as shown by dual-luciferase reporter assays, EMSA, and ChIP-qPCR; IRF1-driven ALOX15B expression promotes ferroptosis in TNBC cells by inhibiting SLC7A11 and GPX4, reducing glutathione, and increasing lipid oxidation. Dual-luciferase reporter assays, EMSA, ChIP-qPCR, siRNA knockdown, ALOX15B overexpression, ferroptosis marker quantification Biochimica et biophysica acta. General subjects Medium 40749811
2026 ALOX15B deficiency in DLBCL cells leads to upregulation of COX-2/PGE2 signaling and downregulation of the TAP1/MHC-I antigen presentation axis, promoting immune evasion; HDAC1/2 occupy the ALOX15B promoter to repress its expression, and HDAC inhibitor tucidinostat restores ALOX15B expression and antigen presentation. siRNA knockdown, luciferase reporter assay, ChIP-seq, ATAC-seq, murine and PDX models, immunohistochemistry Journal of experimental & clinical cancer research Medium 41527135
2025 ALOX15B expression in pulmonary artery endothelial cells is elevated in PAH and promotes endothelial cell proliferation and vascular remodeling; ALOX15B knockdown reduces hypoxia-induced autophagy in mouse PAECs, an effect reversed by PI3K inhibitor, placing ALOX15B upstream of the PI3K/AKT/mTOR pathway in autophagy regulation. siRNA knockdown, PI3K inhibitor treatment, Western blot, right heart catheterization, echocardiography, mouse PAH models (hypoxia ± Sugen5416), systemic knockout mice European journal of pharmacology Medium 41207352
2026 CEBPA directly binds the ALOX15B promoter to transcriptionally activate it; the CEBPA/ALOX15B axis promotes ferroptosis in osteoblasts and contributes to bone loss in postmenopausal osteoporosis via the AMPK/mTOR pathway, as shown by ALOX15B knockout mice subjected to ovariectomy displaying attenuated bone loss and reduced ferroptosis markers. ChIP (CEBPA at ALOX15B promoter), siRNA/overexpression in hFOB 1.19 cells, AMPK/mTOR pathway inhibitors, ALOX15B knockout mouse OVX model, micro-CT, bone density analysis, ferroptosis marker assays Inflammation research Medium 41843143

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma. The American journal of pathology 134 10393855
2006 Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins, leukotrienes, and essential fatty acids 83 16556493
2023 p53 Activates the Lipoxygenase Activity of ALOX15B via Inhibiting SLC7A11 to Induce Ferroptosis in Bladder Cancer Cells. Laboratory investigation; a journal of technical methods and pathology 37 36801644
2016 Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart: IMPLICATIONS FOR MURINE MODELS OF ATHEROSCLEROSIS. The Journal of biological chemistry 36 27435673
2015 Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 25895668
2008 Loss of heterozygosity of 17p13, with possible involvement of ACADVL and ALOX15B, in the pathogenesis of adrenocortical tumors. Annals of surgery 33 18156936
2024 ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2. Redox biology 20 38581859
2020 Brozopine Inhibits 15-LOX-2 Metabolism Pathway After Transient Focal Cerebral Ischemia in Rats and OGD/R-Induced Hypoxia Injury in PC12 Cells. Frontiers in pharmacology 17 32153408
2022 The role of ALOX15B in heat stress-induced apoptosis of porcine sertoli cells. Theriogenology 14 35344833
2022 Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging. Biomedicines 14 35740398
2013 Association of polymorphisms in the ALOX15B gene with coronary artery disease. Clinical biochemistry 12 24373925
2011 Hypoxia promotes rabbit pulmonary artery smooth muscle cells proliferation through a 15-LOX-2 product 15(S)-hydroxyeicosatetraenoic acid. Prostaglandins, leukotrienes, and essential fatty acids 12 22018966
2023 Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models. International journal of molecular sciences 7 37446212
2025 RNAi-based ALOX15B silencing augments keratinocyte inflammation in vitro via EGFR/STAT1/JAK1 signalling. Cell death & disease 6 39843435
2025 KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40569151
2012 Qualitative and Quantitative analysis of 3D predicted arachidonate 15-lipoxygenase-B (15-LOX-2) from Homo sapiens. Bioinformation 4 22829730
2023 Functional Characterization of Mouse and Human Arachidonic Acid Lipoxygenase 15B (ALOX15B) Orthologs and of Their Mutants Exhibiting Humanized and Murinized Reaction Specificities. International journal of molecular sciences 3 37373195
2025 ALOX15 and ALOX15B regulate autophagy to promote pulmonary arterial hypertension via the PI3K/AKT/mTOR pathway. European journal of pharmacology 1 41207352
2026 Low expression of ALOX15B modulates immunosuppressive tumor microenvironment in diffuse large B-cell lymphoma via the TAP1/MHC-I axis. Journal of experimental & clinical cancer research : CR 0 41527135
2026 Targeting CEBPA/ALOX15B attenuates postmenopausal osteoporosis by inhibiting ferroptosis through the AMPK/mTOR signaling pathway. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 0 41843143
2025 The reaction specificity of mammalian ALOX15B orthologs does not depend on the evolutionary ranking of the animals. Journal of lipid research 0 40044044
2025 IRF1 transcriptionally activates ALOX15B to enhance ferroptosis sensitivity in triple-negative breast cancer. Biochimica et biophysica acta. General subjects 0 40749811