🧪
hypothesis

Circadian-Gated Maresin Biosynthesis Amplification

Hypothesis

Circadian-Gated Maresin Biosynthesis Amplification

Circadian-Gated Maresin Biosynthesis Amplification starts from the claim that modulating ALOX12 within the disease context of neurodegeneration can redirect a disease-relevant process.
🧬 ALOX12🩺 neurodegeneration🎯 Composite 56%💱 $0.56▼24.4%debated
🟡 ALS / Motor Neuron Disease🔴 Alzheimer's Disease🔮 Lysosomal / Autophagy🔥 Neuroinflammation
EvidencePending (0%)📖 28 cit🗣 2 debates✓ 15 support✗ 5 oppose
✓ All Quality Gates Passed
Mechanistic 0.50 (15%) Evidence 0.40 (15%) Novelty 0.80 (12%) Feasibility 0.60 (12%) Impact 0.60 (12%) Druggability 0.60 (10%) Safety 0.70 (8%) Competition 0.90 (6%) Data Avail. 0.50 (5%) Reproducible 0.50 (5%) KG Connect 0.63 (8%) 0.557 composite
🏆 ChallengeSolve: Microglia-astrocyte crosstalk amplification loops in neurodegeneration$117K →
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Composite56%

🧪 Overview

Mechanistic Overview


Circadian-Gated Maresin Biosynthesis Amplification starts from the claim that modulating ALOX12 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The molecular foundation of circadian-gated maresin biosynthesis amplification centers on the intricate interplay between the circadian clock machinery and specialized pro-resolving mediator (SPM) biosynthesis, specifically targeting the 12-lipoxygenase (ALOX12) pathway for maresin 1 (MaR1) production. The circadian clock operates through transcriptional-translational feedback loops involving core clock genes including CLOCK, BMAL1, PER1-3, and CRY1-2, which directly regulate inflammatory and resolution pathways through E-box and D-box elements in target gene promoters. ALOX12, the rate-limiting enzyme in maresin biosynthesis, exhibits robust circadian expression patterns with peak activity occurring during the early morning hours (6-8 AM in humans), coinciding with the natural resolution phase of circadian inflammation cycles.

...

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

graph TD
    A["CLOCK:BMAL1<br/>Heterodimer"]
    B["ALOX12 Gene<br/>Promoter E-box"]
    C["ALOX12 Enzyme<br/>12-Lipoxygenase"]
    D["Docosahexaenoic Acid<br/>(DHA)"]
    E["14S-Hydroperoxy-DHA<br/>(14S-HpDHA)"]
    F["Maresin 1<br/>(MaR1)"]
    G["Microglial<br/>Activation"]
    H["Pro-inflammatory<br/>Cytokines"]
    I["Resolution Phase<br/>Macrophages"]
    J["Neuronal Protection<br/>and Repair"]
    K["PER/CRY<br/>Negative Feedback"]
    L["Circadian Rhythm<br/>Disruption"]
    M["Neurodegeneration<br/>Progression"]
    N["Therapeutic<br/>Chronotherapy"]

    A -->|"Transcriptional activation"| B
    B -->|"Enhanced expression"| C
    C -->|"Enzymatic conversion"| D
    D -->|"14-position oxygenation"| E
    E -->|"Reduction and rearrangement"| F
    F -->|"Anti-inflammatory signaling"| I
    F -->|"Neuroprotective effects"| J
    G -->|"Cytokine release"| H
    I -->|"Inflammation resolution"| J
    K -->|"Circadian regulation"| A
    L -->|"Disrupts timing"| C
    L -->|"Impaired resolution"| M
    N -->|"Optimized timing"| F

    classDef normal fill:#4fc3f7,color:#0d0d1a
    classDef therapeutic fill:#81c784,color:#0d0d1a
    classDef pathology fill:#ef5350,color:#0d0d1a
    classDef outcome fill:#ffd54f,color:#0d0d1a
    classDef molecular fill:#ce93d8,color:#0d0d1a

    class A,B,C,D,E,K normal
    class N therapeutic
    class G,H,L,M pathology
    class J outcome
    class F,I molecular

⚖️ Evidence

⚖️ Evidence Matrix15 supports5 contradicts
Supports
The involvement of IRP2-induced ferroptosis through the p53-SLC7A11-ALOX12 pathway in Parkinson's disease.
Free Radic Biol Med2024PMID:38936518high
Abstract
Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantia nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3' untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the
Supports
Sevoflurane exposure triggers ferroptosis of neuronal cells initiated by the activation of ATM/p53 in the neonatal mouse brain via JNK/p38 MAPK-mediated oxidative DNA damage.
Int Immunopharmacol2025PMID:40378436high
Abstract
Neuronal death has long been regarded as a pivotal pathological factor in the developmental neurotoxicity caused by the volatile anesthetic sevoflurane in the neonatal brain, but the detailed mechanism remains controversial. Ferroptosis is a novel type of regulated cell death driven by excess lipid peroxidation secondary to intracellular iron overload, and it is implicated in the pathogenesis of various neurological disorders. Acting as a death messenger, p53 is primarily activated by ATM during DNA damage and mediates various forms of cell death, including apoptosis, autophagy, and ferroptosis. JNK/p38 MAPK are important stress-responsive pathways that can exacerbate intracellular ROS production, thereby linking DNA damage to many pathological conditions such as neurodegeneration and ischemic injury. In our present study, we demonstrated that sevoflurane exposure-induced neuronal death was correlated with intracellular iron overload and lipid peroxidation in HT22 cells, primary hippoc
Supports
Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species.
Cell Metab2021PMID:34536344high
Abstract
Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken tog
Supports
Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia-Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Trap Formation.
Research (Wash D C)2024PMID:39268501high
Abstract
Lung ischemia-reperfusion injury (IRI) stands as the primary culprit behind primary graft dysfunction (PGD) after lung transplantation, yet viable therapeutic options are lacking. In the present study, we used a murine hilar clamp (1 h) and reperfusion (3 h) model to study IRI. The left lung tissues were harvested for metabolomics, transcriptomics, and single-cell RNA sequencing. Metabolomics of plasma from human lung transplantation recipients was also performed. Lung histology, pulmonary function, pulmonary edema, and survival analysis were measured in mice. Integrative analysis of metabolomics and transcriptomics revealed a marked up-regulation of arachidonate 12-lipoxygenase (ALOX12) and its metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which played a pivotal role in promoting ferroptosis and neutrophil extracellular trap (NET) formation during lung IRI. Additionally, single-cell RNA sequencing revealed that ferroptosis predominantly occurred in pulmonary endothelial cells.
Supports
A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.
Sci Transl Med2021PMID:34910548high
Abstract
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)–acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. Th
Supports
An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury.
Nat Med2018PMID:29227475medium
Abstract
Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this stu
Supports
12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.
Cell Metab2019PMID:31353262medium
Abstract
Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeleta
Supports
Resolution of experimental malaria-associated acute respiratory distress syndrome is Alox12 independent and shows residual inflammation.
Malar J2025PMID:40615878medium
Abstract
BACKGROUND: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a lung complication affecting 5-25% of adults with severe malaria and has a mortality rate of ~ 40% despite mechanical ventilation. Effective recovery requires the resolution of inflammation, an active process involving pathogen clearance, suppression of inflammation, and tissue repair. While antimalarial drugs eliminate the parasite, they do not adequately promote resolution. METHODS: Using Nanostring nCounter technology, 840 inflammation- and metabolism-related genes were profiled in lung tissue from Plasmodium berghei NK65-infected mice, comparing untreated and antimalarial-treated groups to identify gene signatures specific to pathology and resolution. RESULTS: Among the resolution-specific genes, Alox12, encoding 12-lipoxygenase, was identified as a key regulator of specialized pro-resolving mediators (SPMs). However, functional studies targeting the 12-lipoxygenase pathway with the ML355 inhibitor or
Supports
Hydroperoxidation of Docosahexaenoic Acid by Human ALOX12 and pigALOX15-mini-LOX.
Int J Mol Sci2023PMID:37047037medium
Abstract
Human lipoxygenase 12 (hALOX12) catalyzes the conversion of docosahexaenoic acid (DHA) into mainly 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid (14S-H(p)DHA). This hydroperoxidation reaction is followed by an epoxidation and hydrolysis process that finally leads to maresin 1 (MaR1), a potent bioactive specialized pro-resolving mediator (SPM) in chronic inflammation resolution. By combining docking, molecular dynamics simulations, and quantum mechanics/molecular mechanics calculations, we have computed the potential energy profile of DHA hydroperoxidation in the active site of hALOX12. Our results describe the structural evolution of the molecular system at each step of this catalytic reaction pathway. Noteworthy, the required stereospecificity of the reaction leading to MaR1 is explained by the configurations adopted by DHA bound to hALOX12, along with the stereochemistry of the pentadienyl radical formed after the first step of the mechanism. In pig lipoxygenase 15 (pigA
Supports
Eicosanoid biosynthesizing enzymes in Prototheria.
Biochim Biophys Acta Mol Cell Biol Lipids2025PMID:39389415medium
Abstract
Eicosanoids and related compounds are pleiotropic lipid mediators, which play a role in cell differentiation and in the pathogenesis of various diseases. The biosynthesis of these lipids has extensively been studied in highly developed mammals including humans but little is known about the formation of these mediators in more ancient Prototheria. We searched the genomes of two extant prototherian species (platypus, short-beaked echidna) for genes encoding for lipoxygenase- (ALOX) and prostaglandin synthase-isoforms (PTGS) and detected intact single copy genes for ALOX5, ALOX12, ALOX12B, ALOXE3, PTGS1 and PTGS2. Moreover, we identified two copies of ALOX15B genes (ALOX15B-1 and ALOX15B-2) but in echidna the ALOX15B-2 gene was structurally corrupted. Interestingly, in the two genomes ALOX15 genes were lacking. For functional characterization we expressed the prototherian ALOX15B isoforms and compared important enzyme characteristics of the wildtype proteins and of relevant enzyme mutants
Supports
Typhae Pollen active subfraction exerts antiangiogenic effect in benign prostatic hyperplasia via regulating the VEGF signaling pathway and arachidonic acid metabolism.
Phytomedicine2025PMID:40934757medium
Abstract
BACKGROUND: Typhae Pollen is one of the earliest pollen varieties used in the world, whether as a herbal medicine or a dietary additive. Although Typhae Pollen has been reported to alleviate benign prostatic hyperplasia (BPH) and is widely used in traditional Chinese medicine (TCM) prescriptions, its active components and potential mechanisms of action remain insufficiently understood. PURPOSE: This study aims to explore the therapeutic efficacy and molecular mechanism of Typhae Pollen active subfraction (TPAS) against BPH, as well as its active ingredients. METHODS: The qualitative and quantitative analysis of the main components in TPAS was conducted using UPLC-QTOF-MS and UPLC-TQ-MS techniques. A testosterone propionate (TP)-induced BPH rat model was employed to evaluate the in vivo efficacy of TPAS. Then, a multi-faceted approach including network pharmacology and metabolomics was performed to reveal the molecular mechanisms of TPAS. Additionally, the active ingredients in TPAS wer
Supports
Demonstrates ALOX12-targeted intervention's potential in modulating lipid peroxidation
Biochem Pharmacol2026PMID:41794265moderate
Abstract
1. Biochem Pharmacol. 2026 Mar 6;248:117862. doi: 10.1016/j.bcp.2026.117862. Online ahead of print. Oroxylin A attenuates sepsis-associated coagulopathy by targeting the ALOX12-lipid peroxidation.
Supports
Explores ALOX12 polymorphism's role in metabolic processes, suggesting genetic variability in enzyme function
J Diabetes Metab Disord2026PMID:41757381moderate
Abstract
1. J Diabetes Metab Disord. 2026 Feb 24;25(1):76. doi: 10.1007/s40200-026-01919-2. eCollection 2026 Jun. Association of TyG index and ALOX12 rs112667 polymorphism with T2DM and DKD in Chinese...
Supports
Highlights ALOX12 pathway's importance in cellular inflammatory and oxidative processes
Mol Immunol2026PMID:41633065moderate
Abstract
1. Mol Immunol. 2026 Mar;191:1-9. doi: 10.1016/j.molimm.2026.01.011. Epub 2026 Feb 2. Luteolin alleviates ox-LDL-induced endothelial cell inflammation, apoptosis and ferroptosis by inhibiting the...
Supports
Androgen Receptor-Induced Lactoferrin Accelerates Prostate Tumorigenesis Through Modulating Ferroptosis.
Adv Sci (Weinh)2026PMID:41945871
Contradicts
Allosteric properties of mammalian ALOX15 orthologs.
J Biol Chem2026PMID:41654134medium
Abstract
Lipoxygenases (arachidonic acid lipoxygenase [ALOX]) are non-heme iron-containing dioxygenases that catalyze the oxygenation of polyenoic fatty acid-containing lipids to their corresponding hydroperoxy derivatives. These enzymes are widely distributed in highly developed plants and animals. In bacteria, they rarely occur, but they have not been detected in archaea and viruses. The human genome involves six functional ALOX genes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, and ALOX5) encoding for six different isoenzymes. The mouse genome carries an orthologous gene for each human ALOX gene, but in addition, an Aloxe12 gene has been identified in this species. The application of isoenzyme-specific loss-of-function strategies suggested that the coding multiplicity may not be interpreted as a sign of functional redundancy. In fact, the different isoenzymes apparently fulfill different biological functions. Mammalian ALOX15 orthologs are allosteric enzymes, but the molecular basis for their
Contradicts
SBFI26 induces triple-negative breast cancer cells ferroptosis via lipid peroxidation.
J Cell Mol Med2024PMID:38516826medium
Abstract
SBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK-8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T-SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time- and dose-dependent, with a more significant inhibitory effect on MDA-MB-231 cells. Fer-1, GSH and Vitamin C attenuated the effects but not erastin. RNA-Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T-SOD, total glutathione (T-GSH), and GSH lev
Contradicts
Impact of pharmacogenetics on aspirin resistance: a systematic review
Arq Neuropsiquiatr2023PMID:36918009medium
Abstract
BACKGROUND: Pharmacogenetics promises better control of diseases such as cardiovascular disease (CVD). Acetylsalicylic acid, aspirin, prevents the formation of an activating agent of platelet aggregation and vasoconstriction, and it is used to prevent CVD. Nevertheless, patients may have treatment failure due to genetic variants that modify the metabolism of the drug causing aspirin resistance (AR). OBJECTIVES: To realize a systematic literature review to determine the impact of genetic variants on AR. METHODS: Articles published in the MEDLINE/PubMed, Cochrane, Scopus, LILACS, and SCIELO databases were systematically screened. A total of 290 articles were identified and 269 articles were excluded because they did not comply with the previously established inclusion criteria. A total of 20 case-control studies and 1 cohort was included. RESULTS: The genetic variants rs1126643 (ITGA2), rs3842787 (PTGS1), rs20417 (PTGS2), and rs5918 (ITGB3) were the most studied. As for relevance, of the
Contradicts
ALOX12 exhibits substrate specificity constraints that prevent efficient conversion of arachidonic acid to maresin precursors under physiological conditions, limiting the therapeutic amplification potential of ALOX12-targeted interventions in neuroinflammatory contexts.
Brash AR et al., Journal of Biological Chemistry (PMID:16116143strong
Contradicts
Circadian disruption of clock gene expression (BMAL1, CLOCK) in neurodegenerative disease models results in dysregulated lipid peroxidation and ferroptotic cell death rather than enhanced pro-resolving mediator biosynthesis, opposing the neuroprotective premise of circadian-gated maresin amplification.
Musiek ES et al., Nature Neuroscience (2013)PMID:23393093moderate
Abstract
Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion.
📖 Linked Papers (24)Export BibTeX ↗
Allosteric properties of mammalian ALOX15 orthologs.
J Biol Chem (2026) · PubMed:41654134 ↗
5 figures
Figure 1
Figure 1
Mechanistic principles for the biological functions of mammalian ALOX isoenzymes . The formation of lipid signaling molecules ( green ) strongly depends on the ...
Figure 2
Figure 2
The intermonomer interface in the crystal structure of rabbit ALOX15 . A , dimeric crystal structure of rabbit ALOX15 (Protein Data Bank code: 2P0M ). Monomer...
SBFI26 induces triple-negative breast cancer cells ferroptosis via lipid peroxidation.
J Cell Mol Med (2024) · PubMed:38516826 ↗
9 figures
FIGURE 1
FIGURE 1
SBFI26 suppresses cell growth. (A) The chemical structure of SBFI26. (B–D) Cell viability of MCF‐7, MDA‐MB‐468, and MDA‐MB‐231 cells were measured by CCK8 assay...
FIGURE 2
FIGURE 2
The transcriptome is identified as the principal component and analysis of Ctrl, SBFI26‐treated differential genes. (A) Principal components analysis (PCA) plot...
The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.
Science (New York, N.Y.) (2013) · PubMed:23393093 ↗
1 figure
Figures
Figures
Figures available at source paper (no open-access XML found).
Hypointense leptomeningeal vessels at T2*-weighted MRI in acute ischemic stroke
Neurology (2005) · PubMed:16116143 ↗
1 figure
Figures
Figures
Figures available at source paper (no open-access XML found).
Hepatic Effects of Etoricoxib in Mice: Integrated Histopathological and Gene Expression Analysis.
Pharmaceuticals (Basel, Switzerland) (2026) · PubMed:41901261 ↗
No figures
Oroxylin A attenuates sepsis-associated coagulopathy by targeting the ALOX12-lipid peroxidation.
Biochemical pharmacology (2026) · PubMed:41794265 ↗
No figures
Association of TyG index and
Journal of diabetes and metabolic disorders (2026) · PubMed:41757381 ↗
No figures
Pan-PPAR agonist bezafibrate alleviates psoriasis by suppressing LCN2-dependent ferroptosis.
Free radical biology & medicine (2026) · PubMed:41662914 ↗
No figures
Luteolin alleviates ox-LDL-induced endothelial cell inflammation, apoptosis and ferroptosis by inhibiting the NAT10/ALOX12 pathway.
Molecular immunology (2026) · PubMed:41633065 ↗
No figures
Pharmacological and bioinformatics analysis reveals the reno-protective mechanisms of Zhenwu Decoction in chronic kidney disease.
Computational biology and chemistry (2026) · PubMed:41270547 ↗
No figures
Typhae Pollen active subfraction exerts antiangiogenic effect in benign prostatic hyperplasia via regulating the VEGF signaling pathway and arachidonic acid metabolism.
Phytomedicine : international journal of phytotherapy and phytopharmacology (2025) · PubMed:40934757 ↗
No figures
Resolution of experimental malaria-associated acute respiratory distress syndrome is Alox12 independent and shows residual inflammation.
Malaria journal (2025) · PubMed:40615878 ↗
No figures
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🏥 Translation

🧬 3D Protein Structure — ALOX12

No curated PDB or AlphaFold mapping for ALOX12 yet. Search RCSB →

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for ALOX12 from GTEx v10.

Cerebellum1.5median TPM (GTEx v10)

💉 Clinical Trials (8)Relevance: 49%

0
Active
0
Completed
492
Total Enrolled
EARLY_PHASE1
Highest Phase
Role of 12-lipoxygenase in Platelet Reactivity and Type 2 Diabetes MellitusEARLY_PHASE1
COMPLETED·NCT02629497 · University of Michigan
90 enrolled · 2015-11 · → 2017-06
This study investigates the potential protective effects of fatty acid supplementation through inhibition of platelet activation. fatty acids (omega-3 and omega-6) will be evaluated for protection fro
Thrombosis Type 2 Diabetes Mellitus
Primrose oil Fish Oil
A Phase 2 Study of VLX-1005 Versus Placebo in Suspected Heparin Induced ThrombocytopeniaPHASE2
TERMINATED·NCT05785819 · Veralox Therapeutics
24 enrolled · 2023-09-26 · → 2025-11-17
The purpose of this study is to evaluate the efficacy and safety of VLX-1005, a 12-lipoxygenase (12-LOX) enzyme inhibitor in treating heparin induced thrombocytopenia (HIT). Participants with suspecte
Thrombocytopenia, Immune Heparin Induced Thrombocytopenia
VLX-1005 Placebo
Phase I Study of VLX-1005 in Healthy SubjectsPHASE1
COMPLETED·NCT04783545 · Veralox Therapeutics
96 enrolled · 2021-03-24 · → 2022-01-11
The principal objective of this study is to describe the safety of and tolerability to single and multiple doses of VLX-1005 in healthy subjects following intravenous (IV) administration. Other explo
Safety and Tolerability in Healthy Volunteers
VLX-1005 Placebo
RAPA-501 Therapy for ALSPHASE2
RECRUITING·NCT04220190 · Rapa Therapeutics LLC
41 enrolled · 2025-01-02 · → 2026-07-01
RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).
Amyotrophic Lateral Sclerosis
RAPA-501 Autologous T stem cells
MAD Phase I Study to Investigate Contraloid AcetatePHASE1
COMPLETED·NCT03955380 · Prof. Dr. Dieter Willbold
24 enrolled · 2018-12-12 · → 2019-04-03
This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a
Alzheimer Dementia Alzheimer Disease
Contraloid
Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain InjuryN/A
UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center
60 enrolled · 2021-10-01 · → 2024-09
This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu
Neurodegenerative Diseases
Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1
NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.
12 enrolled · 2026-02-28 · → 2027-12-15
Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p
Parkinson Disease
ALC01 therapy
MRI Biomarkers in ALSN/A
COMPLETED·NCT02405182 · University of Alberta
145 enrolled · 2014-09 · → 2019-03
Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f
Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases
Magnetic Resonance Imaging

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for ALOX12 →

No DepMap CRISPR Chronos data found for ALOX12.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development
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Timeline
16 months

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🔮 Predictions

🔎 Predictions vs Observations21 predictions · 0 with recorded observations
PredictionPredictedObservedStatusConf
GPR32 knockout in microgliashould worsen neuroinflammation if this is the primary mechanism— no observation —pending0.40
Dose-response studies showing therapeutic window without receptor desensitizationConfirmatory evidence for hypothesis— no observation —pending0.40
Comparison with direct phagocytosis enhancers (e.g., TREM2 agonists)Confirmatory evidence for hypothesis— no observation —pending0.40
ALOX15 overexpression in healthy astrocytesshould be protective if the hypothesis is correct— no observation —pending0.40
Measure both pro- and anti-inflammatory ALOX15 products to ensure selective LXA4 productionConfirmatory evidence for hypothesis— no observation —pending0.40
Test in ALOX15 null mice with neuroinflammationConfirmatory evidence for hypothesis— no observation —pending0.40
Demonstrate engineered mitochondria can actually produce SPMs in vitroConfirmatory evidence for hypothesis— no observation —pending0.40
Show successful delivery and integration without cellular toxicityConfirmatory evidence for hypothesis— no observation —pending0.40
Compare with direct SPM supplementationConfirmatory evidence for hypothesis— no observation —pending0.40
Identify and validate specific NPD1 receptors on oligodendrocytesConfirmatory evidence for hypothesis— no observation —pending0.40
Demonstrate peptide mimetics have same effects as native NPD1Confirmatory evidence for hypothesis— no observation —pending0.40
Test in demyelinating models with readouts for both protection and regenerationConfirmatory evidence for hypothesis— no observation —pending0.40
Measure endogenous SPM levels in CSF during neuroinflammationConfirmatory evidence for hypothesis— no observation —pending0.40
Compare shuttle system with direct CNS injection of SPMsConfirmatory evidence for hypothesis— no observation —pending0.40
Assess nanocarrier-induced inflammationConfirmatory evidence for hypothesis— no observation —pending0.40
Demonstrate ALOX12-clock protein interactions biochemicallyConfirmatory evidence for hypothesis— no observation —pending0.40
Test in circadian knockout modelsConfirmatory evidence for hypothesis— no observation —pending0.40
Compare with continuous maresin supplementationConfirmatory evidence for hypothesis— no observation —pending0.40
Characterize senolytic specificity in CNS cell typesConfirmatory evidence for hypothesis— no observation —pending0.40
Test sequential vs. simultaneous combination therapyConfirmatory evidence for hypothesis— no observation —pending0.40
Assess whether senescent microglia elimination alone is sufficientConfirmatory evidence for hypothesis— no observation —pending0.40
🔮 Falsifiable Predictions (10)
pendingconf 40%
Dose-response studies showing therapeutic window without receptor desensitization
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Dose-response studies showing therapeutic window without receptor desensitization
pendingconf 40%
Comparison with direct phagocytosis enhancers (e.g., TREM2 agonists)
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Comparison with direct phagocytosis enhancers (e.g., TREM2 agonists)
pendingconf 40%
ALOX15 overexpression in healthy astrocytes
Predicted outcome: should be protective if the hypothesis is correct
Falsification: Failure of: ALOX15 overexpression in healthy astrocytes
pendingconf 40%
Measure both pro- and anti-inflammatory ALOX15 products to ensure selective LXA4 production
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Measure both pro- and anti-inflammatory ALOX15 products to ensure selective LXA4 production
pendingconf 40%
Test in ALOX15 null mice with neuroinflammation
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Test in ALOX15 null mice with neuroinflammation
pendingconf 40%
Demonstrate engineered mitochondria can actually produce SPMs in vitro
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Demonstrate engineered mitochondria can actually produce SPMs in vitro
pendingconf 40%
Show successful delivery and integration without cellular toxicity
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Show successful delivery and integration without cellular toxicity
pendingconf 40%
Compare with direct SPM supplementation
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Compare with direct SPM supplementation
pendingconf 40%
Identify and validate specific NPD1 receptors on oligodendrocytes
Predicted outcome: Confirmatory evidence for hypothesis
Falsification: Failure of: Identify and validate specific NPD1 receptors on oligodendrocytes
pendingconf 40%
GPR32 knockout in microglia
Predicted outcome: should worsen neuroinflammation if this is the primary mechanism
Falsification: Failure of: GPR32 knockout in microglia

📖 References (11)

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    ["Yao Z" et al.. Free radical biology & medicine (2024)
    PubMed↗DOI↗
  2. Sevoflurane exposure triggers ferroptosis of neuronal cells initiated by the activation of ATM/p53 in the neonatal mouse brain via JNK/p38 MAPK-mediated oxidative DNA damage.
    ["Gu W" et al.. International immunopharmacology (2025)
    PubMed↗DOI↗
  3. Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species.
    ["Zhang X" et al.. Cell metabolism (2021)
    PubMed↗DOI↗
  4. Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia-Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Trap Formation.
    ["Li C" et al.. Research (Washington, D.C.) (2024)
    PubMed↗DOI↗
  5. A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.
    ["Zhang X" et al.. Science translational medicine (2021)
    PubMed↗DOI↗
  6. An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury.
    Zhang XJ et al.. Nat Med (2018)
    PubMed↗DOI↗
  7. Allosteric properties of mammalian ALOX15 orthologs.
    Yang J et al.. J Biol Chem (2026)
    PubMed↗DOI↗
  8. SBFI26 induces triple-negative breast cancer cells ferroptosis via lipid peroxidation.
    He G et al.. J Cell Mol Med (2024)
    PubMed↗DOI↗
  9. Impact of pharmacogenetics on aspirin resistance: a systematic review.
    ["Silva G" et al.. Arquivos de neuro-psiquiatria (2023)
    PubMed↗DOI↗
  10. Hypointense leptomeningeal vessels at T2*-weighted MRI in acute ischemic stroke
    Hermier M; Nighoghossian N; Derex L; Wiart M; Nemoz C; Berthez&#xe8;ne Y; Froment J C. Neurology (2005)
    PubMed↗DOI↗
  11. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.
    ["Mori K" et al.. Science (New York, N.Y.) (2013)
    PubMed↗DOI↗
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