GO:0019369 arachidonate metabolic process: Lipid Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0019369 arachidonate metabolic process describes the chemical reactions and pathways involving arachidonic acid, a 20-carbon straight-chain fatty acid with four double bonds.
• Arachidonic acid is released from membrane phospholipids and converted by cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes into eicosanoids that drive inflammation, pain, and tissue repair [1,6].
• Key enzymes include ALOX5, ALOX12, ALOX15, ALOX15B, ALOX8, PTGS1, PTGS2, CYP2C, CYP2J, ACSL4, LPCAT3, and PLA2 family members [2,3,6,7].
• Dysregulated arachidonate metabolism is implicated in myocardial infarction, allergic inflammation, ischemic stroke, hepatocellular carcinoma, and anthracycline-resistant breast cancer [1,3,5,7,8].
• Arachidonic acid can induce ferroptosis through the SIRT5-ACSL4/LPCAT3/ALOX15 axis, linking lipid metabolism to regulated cell death.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable causal dissection of arachidonate metabolic enzymes in disease [1,3,5,8].
Description
Arachidonate metabolic process (GO:0019369) is the biological process encompassing all chemical reactions and pathways involving arachidonic acid, a straight-chain fatty acid with 20 carbon atoms and four double bonds per molecule, specifically the all-Z-(5,8,11,14)-isomer. This process is central to lipid signaling because arachidonic acid serves as the substrate for multiple enzyme families that generate eicosanoids, including prostaglandins, leukotrienes, lipoxins, and hydroxy-eicosatetraenoic acids [6,7]. These lipid mediators act locally as autacoids and play essential roles in inflammation, immunity, vascular tone, and cell survival [1,6]. Researchers study GO:0019369 because its dysregulation is a hallmark of many human diseases. For example, after myocardial infarction, arachidonic acid fuels inflammation by unlocking macrophage protein phosphatase 5, revealing a direct link between lipid metabolism and innate immune activation. In allergic diseases, leukotrienes derived from arachidonic acid are major drivers of bronchoconstriction and mucus secretion. In cancer, arachidonic acid induces ferroptosis in hepatocellular carcinoma via the SIRT5-ACSL4/LPCAT3/ALOX15 axis, leading to lipid peroxidation and mitochondrial dysfunction. Cross-platform meta-analysis has also identified arachidonic acid metabolism genes as part of expression signatures in acquired anthracycline-resistant breast cancer. The process is also relevant to ischemic stroke, where 12/15-lipoxygenase has emerged as a key mediator of neuroinflammation and neuronal injury. Plant extracts that inhibit lipoxygenases are being explored as anti-inflammatory agents, underscoring the therapeutic potential of targeting this pathway. Understanding the enzymes, substrates, and regulatory mechanisms of arachidonate metabolic process is therefore essential for developing new treatments for inflammatory, cardiovascular, and neoplastic diseases.
arachidonate metabolic process At A Glance
| GO ID | GO:0019369 |
|---|---|
| GO term | arachidonate metabolic process |
| Ontology | biological_process |
| Synonym | arachidonic acid metabolic process; arachidonic acid metabolism |
| Definition | The chemical reactions and pathways involving arachidonic acid, a straight chain fatty acid with 20 carbon atoms and four double bonds per molecule. Arachidonic acid is the all-Z-(5,8,11,14)-isomer. |
| Major function | Production of eicosanoid lipid mediators that regulate inflammation, immunity, vascular tone, and cell death [1,6,7]. |
| Key enzymes | ALOX5, ALOX12, ALOX15, ALOX15B, ALOX8, PTGS1, PTGS2, CYP2C, CYP2J, ACSL4, LPCAT3, PLA2 family [2,3,6,7]. |
| Associated diseases | Myocardial infarction, allergic diseases, ischemic stroke, hepatocellular carcinoma, anthracycline-resistant breast cancer [1,3,5,7,8]. |
| Research methods | CRISPR knockout, point mutation, knock-in, overexpression, lipidomics, RNA-seq, ferroptosis assays [1,3,5,8]. |
What Is GO:0019369?
GO:0019369 arachidonate metabolic process is defined as the chemical reactions and pathways involving arachidonic acid, a straight chain fatty acid with 20 carbon atoms and four double bonds per molecule. Arachidonic acid is the all-Z-(5,8,11,14)-isomer. This biological process includes the release of arachidonic acid from membrane phospholipids, its enzymatic oxygenation by cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases, and the subsequent conversion of intermediates into bioactive eicosanoids such as prostaglandins, leukotrienes, lipoxins, and hydroxyeicosatetraenoic acids [1,6,7].
Why Is arachidonate metabolic process Important in Cell Biology?
Arachidonate metabolic process is critically important because it generates a diverse family of lipid mediators that control fundamental physiological and pathological processes, including inflammation, allergy, pain, blood clotting, and cell death [1,6,7]. Dysregulation of this pathway contributes to cardiovascular disease, asthma, stroke, and cancer, making its enzymes attractive drug targets [1,3,5,7,8]. Moreover, the discovery that arachidonic acid can trigger ferroptosis through ACSL4, LPCAT3, and ALOX15 has linked this metabolic process to regulated cell death and opened new avenues for cancer therapy.
• Arachidonic acid is the precursor to prostaglandins, leukotrienes, lipoxins, and other eicosanoids that mediate inflammation and immunity [6,7].
• The pathway is activated after myocardial infarction, where arachidonic acid unlocks macrophage protein phosphatase 5 to fuel inflammation.
• Leukotrienes produced via arachidonate metabolism are central to allergic diseases such as asthma and allergic rhinitis.
• 12/15-lipoxygenase, a key enzyme in this process, contributes to ischemic stroke pathology.
• Arachidonic acid induces ferroptosis in hepatocellular carcinoma via the SIRT5-ACSL4/LPCAT3/ALOX15 axis.
• Expression signatures of arachidonic acid metabolism genes are associated with anthracycline resistance in breast cancer.
• Lipoxygenase inhibitors from plant extracts are being investigated as anti-inflammatory therapeutics.
• The pathway is a source of lipid peroxidation products that can cause mitochondrial dysfunction.
• Enzymes such as ALOX8 and ALOX15 are potential targets for modulating inflammation and cancer progression [2,3].
• CRISPR-based models allow precise dissection of causal roles of arachidonate metabolic genes in disease [1,3,5,8].
What Happens During arachidonate metabolic process?
Release of arachidonic acid from membrane phospholipids
In simple terms: Arachidonic acid is cut out of the cell membrane before it can be used.
Arachidonic acid is esterified at the sn-2 position of membrane glycerophospholipids. Phospholipase A2 enzymes hydrolyze this bond to release free arachidonic acid, which then becomes available for enzymatic oxygenation [1,6]. This step is rate-limiting and is tightly regulated by calcium and phosphorylation signals. In macrophages after myocardial infarction, arachidonic acid release is linked to the activation of protein phosphatase 5, which amplifies inflammatory signaling.
Cyclooxygenase pathway
In simple terms: One set of enzymes turns arachidonic acid into prostaglandins that cause pain and inflammation.
Cyclooxygenases PTGS1 and PTGS2 convert arachidonic acid into prostaglandin H2, which is further metabolized by specific synthases into prostaglandins (PGE2, PGD2, PGF2alpha, PGI2) and thromboxane A2. These mediators regulate pain, fever, vascular tone, and platelet aggregation. PTGS2 is induced by inflammatory stimuli and is the target of nonsteroidal anti-inflammatory drugs.
Lipoxygenase pathway
In simple terms: Another set of enzymes makes leukotrienes and lipoxins that drive allergy and resolve inflammation.
Lipoxygenases insert molecular oxygen into arachidonic acid at specific positions. ALOX5 initiates the 5-lipoxygenase pathway leading to leukotrienes, which are potent bronchoconstrictors and chemoattractants in allergic diseases. ALOX12 and ALOX15 generate 12-HETE and 15-HETE, respectively, and are involved in inflammation and stroke. ALOX15 also participates in the synthesis of lipoxins, which have anti-inflammatory and pro-resolving actions. ALOX8 is an 8(S)-lipoxygenase that produces 8-HETE.
Cytochrome P450 pathway
In simple terms: A third set of enzymes makes molecules that affect blood pressure and vascular tone.
Cytochrome P450 epoxygenases (CYP2C and CYP2J subfamilies) convert arachidonic acid into epoxyeicosatrienoic acids (EETs), while omega-hydroxylases produce 20-HETE. EETs are vasodilatory and anti-inflammatory, whereas 20-HETE is vasoconstrictive. These mediators play important roles in cardiovascular and renal physiology.
Ferroptosis and lipid peroxidation
In simple terms: When arachidonic acid is oxidized too much, it can cause a form of cell death called ferroptosis.
Arachidonic acid can be incorporated into membrane phospholipids by ACSL4 and LPCAT3, and then oxidized by ALOX15 to trigger ferroptosis, an iron-dependent form of cell death. In hepatocellular carcinoma, this process is regulated by SIRT5 and leads to lipid peroxidation and mitochondrial dysfunction. This links arachidonate metabolic process directly to regulated cell death and cancer therapy.
Key Genes Involved in GO:0019369 arachidonate metabolic process
The following genes encode enzymes and transporters that directly participate in arachidonate metabolic process, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ALOX5 | Initiates 5-lipoxygenase pathway to leukotrienes | Allergic diseases, asthma, inflammation |
| ALOX12 | Produces 12-HETE from arachidonic acid | Ischemic stroke, inflammation |
| ALOX15 | Produces 15-HETE and lipoxins; drives ferroptosis | Cancer, ferroptosis, inflammation [3,6] |
| ALOX15B | Produces 15-HETE with different stereochemistry | Cancer, inflammation |
| ALOX8 | 8(S)-lipoxygenase producing 8-HETE | Lipid signaling research |
| PTGS1 | Constitutive cyclooxygenase for prostaglandin synthesis | Pain, inflammation, platelet function |
| PTGS2 | Inducible cyclooxygenase in inflammation | Inflammation, cancer, NSAID target |
| CYP2C | Epoxygenase producing EETs | Cardiovascular and renal physiology |
| CYP2J | Epoxygenase producing EETs | Cardiovascular protection |
| ACSL4 | Activates arachidonic acid for phospholipid incorporation | Ferroptosis, cancer |
| LPCAT3 | Incorporates arachidonic acid into phospholipids | Ferroptosis, lipid metabolism |
| SIRT5 | Regulates ACSL4/LPCAT3/ALOX15 axis | Ferroptosis in hepatocellular carcinoma |
| PLA2G4A | Releases arachidonic acid from phospholipids | Inflammation, eicosanoid production [1,6] |
| PLA2G2A | Secretory phospholipase A2 | Inflammation, host defense |
| ALOX5AP | Scaffold protein for 5-lipoxygenase activation | Leukotriene biosynthesis, allergy |
| LTA4H | Converts leukotriene A4 to leukotriene B4 | Inflammation, allergy |
| CBR1 | Carbonyl reductase involved in prostaglandin metabolism | Eicosanoid metabolism |
How Is arachidonate metabolic process Regulated?
Arachidonate metabolic process is regulated at multiple levels. Phospholipase A2 activity is controlled by calcium and phosphorylation, determining the availability of free arachidonic acid [1,6]. Cyclooxygenase and lipoxygenase enzymes are regulated by transcriptional induction (e.g., PTGS2 by inflammatory stimuli) and by post-translational modifications [6,7]. In macrophages after myocardial infarction, arachidonic acid promotes inflammation by unlocking protein phosphatase 5, revealing a direct regulatory link between lipid metabolism and phosphatase signaling. Additionally, SIRT5 regulates the ACSL4/LPCAT3/ALOX15 axis to control ferroptosis in hepatocellular carcinoma. The 12/15-lipoxygenase pathway is also regulated in ischemic stroke, where its activity influences neuroinflammation.
arachidonate metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ALOX5 | Allergic asthma, leukotriene biosynthesis | Knockout mouse or human cell line with ALOX5 KO |
| ALOX15 | Hepatocellular carcinoma, ferroptosis | Overexpression or point-mutation in HepG2 cells |
| ACSL4 | Ferroptosis, lipid peroxidation | CRISPR knockout in cancer cell lines |
| PTGS2 | Inflammation, cancer | Knock-in reporter for PTGS2 expression |
| ALOX12 | Ischemic stroke, neuroinflammation | Knockout in neuronal cell models |
Cardiovascular disease and myocardial infarction
After myocardial infarction, arachidonic acid fuels inflammation by unlocking macrophage protein phosphatase 5, which amplifies inflammatory cytokine production and worsens cardiac injury. This identifies arachidonate metabolic process as a therapeutic target in cardiovascular disease.
Allergic diseases and asthma
Leukotrienes derived from arachidonic acid via the 5-lipoxygenase pathway are major mediators of allergic inflammation, bronchoconstriction, and mucus secretion. Antileukotriene drugs are used clinically for asthma, validating this pathway as a drug target.
Ischemic stroke and neuroinflammation
12/15-lipoxygenase, a key enzyme in arachidonate metabolic process, has emerged as a mediator of ischemic stroke pathology, contributing to oxidative stress and neuronal death. Inhibiting this enzyme may offer neuroprotection.
Cancer and ferroptosis
Arachidonic acid induces ferroptosis in hepatocellular carcinoma via the SIRT5-ACSL4/LPCAT3/ALOX15 axis, leading to lipid peroxidation and mitochondrial dysfunction. Expression signatures of arachidonic acid metabolism genes are also associated with anthracycline resistance in breast cancer. These findings suggest that modulating this pathway could improve cancer therapy.
From arachidonate metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of ALOX15 protect against ferroptosis? | ALOX15 knockout cell line |
| Does a point mutation in ACSL4 alter lipid peroxidation? | ACSL4 point-mutation knock-in |
| Can overexpression of PTGS2 drive inflammation? | PTGS2 overexpression cell model |
| Does ALOX5 knockout reduce leukotriene production? | ALOX5 knockout in mast cells or macrophages |
| Does SIRT5 regulate the ACSL4/LPCAT3/ALOX15 axis? | SIRT5 knockout or overexpression |
| Does 12/15-lipoxygenase inhibition reduce stroke injury? | ALOX15 knockout mouse |
How to Study the arachidonate metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS/MS lipidomics | Arachidonic acid and eicosanoid levels | Quantifying pathway activity in cells and tissues [1,3] |
| CRISPR knockout screening | Genes required for arachidonate-induced phenotypes | Identifying ferroptosis regulators |
| RNA-seq | Transcriptional changes in arachidonate metabolic genes | Disease signature discovery |
| C11-BODIPY staining | Lipid peroxidation | Ferroptosis detection |
| Western blot | Protein expression of ALOX, PTGS, ACSL4 | Validating knockout or overexpression [1,3] |
| ELISA | Prostaglandin and leukotriene levels | Inflammation studies [6,7] |
| Immunofluorescence | Subcellular localization of enzymes | Tissue imaging |
| Seahorse assay | Mitochondrial function | Metabolic dysfunction assessment |
Lipidomics and mass spectrometry
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used to quantify arachidonic acid and its metabolites, including prostaglandins, leukotrienes, and HETEs, providing a comprehensive readout of pathway activity [1,3,6].
CRISPR-based genetic screens
Genome-wide CRISPR knockout screens can identify genes that regulate arachidonic acid-induced phenotypes such as ferroptosis or inflammation, enabling unbiased discovery of pathway components [3,5].
RNA-seq and transcriptomics
RNA sequencing reveals expression changes in arachidonate metabolic genes under disease conditions, as shown in meta-analysis of anthracycline-resistant breast cancer.
Ferroptosis and lipid peroxidation assays
Lipid peroxidation is measured using C11-BODIPY or malondialdehyde assays, and ferroptosis is assessed by cell viability rescue with ferrostatin-1, as demonstrated in hepatocellular carcinoma studies.
How CRISPR Can Be Used to Study GO:0019369 arachidonate metabolic process
Knockout
CRISPR knockout of arachidonate metabolic genes such as ALOX15, ACSL4, or PTGS2 allows researchers to determine their causal role in inflammation, ferroptosis, and cancer. For example, ALOX15 knockout reduces lipid peroxidation and ferroptosis in hepatocellular carcinoma cells.
Point Mutation
Point mutations can be introduced into catalytic residues of enzymes like ALOX5 or ACSL4 to dissect their enzymatic activity from scaffolding functions. This is valuable for understanding how specific amino acids contribute to arachidonic acid metabolism.
Knock-in
Knock-in of tagged versions of enzymes (e.g., GFP-ALOX15) enables live-cell imaging and proteomic analysis of arachidonate metabolic complexes. Knock-in of disease-associated variants can model human mutations [1,3].
Overexpression
Overexpression of PTGS2 or ALOX5 in cell lines can amplify eicosanoid production and model inflammatory diseases. This approach is useful for screening inhibitors of arachidonic acid metabolism [6,7].
How EDITGENE Supports arachidonate metabolic process Research
Researchers studying arachidonate metabolic process-related genes often need to determine whether a candidate gene is causally involved in disease phenotypes such as inflammation, ferroptosis, or cancer progression. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling rigorous functional validation of genes in this pathway.
Contact EDITGENE today to design your custom CRISPR model for arachidonate metabolic process research.
Frequently Asked Questions About arachidonate metabolic process
What is arachidonate metabolic process GO:0019369?
It is the biological process comprising all chemical reactions and pathways involving arachidonic acid, a 20-carbon fatty acid with four double bonds, leading to eicosanoid production [1,6].
What genes are involved in arachidonate metabolic process?
Key genes include ALOX5, ALOX12, ALOX15, ALOX15B, ALOX8, PTGS1, PTGS2, CYP2C, CYP2J, ACSL4, LPCAT3, PLA2G4A, and SIRT5 [2,3,6,7].
How is arachidonic acid released from membranes?
Phospholipase A2 enzymes hydrolyze arachidonic acid from the sn-2 position of membrane phospholipids [1,6].
What diseases are linked to arachidonate metabolic process?
It is linked to myocardial infarction, allergic asthma, ischemic stroke, hepatocellular carcinoma, and anthracycline-resistant breast cancer [1,3,5,7,8].
What is the role of ALOX15 in ferroptosis?
ALOX15 oxidizes arachidonic acid-containing phospholipids to drive lipid peroxidation and ferroptosis in cancer cells.
How can CRISPR be used to study arachidonate metabolism?
CRISPR knockout, point mutation, knock-in, and overexpression models allow causal testing of genes like ACSL4, ALOX15, and PTGS2 in disease phenotypes [1,3,5,8].
What are leukotrienes and how are they made?
Leukotrienes are eicosanoids produced from arachidonic acid via the 5-lipoxygenase pathway, and they drive allergic inflammation.
Is arachidonic acid involved in stroke?
Yes, 12/15-lipoxygenase metabolizes arachidonic acid in ischemic stroke, contributing to neuroinflammation and injury.
What methods measure arachidonic acid metabolites?
LC-MS/MS lipidomics, ELISA, and C11-BODIPY staining are commonly used to quantify eicosanoids and lipid peroxidation [1,3,6].
Can plant extracts inhibit arachidonate metabolism?
Yes, plant extracts have been shown to inhibit lipoxygenases, suggesting anti-inflammatory potential.
Conclusion
Arachidonate metabolic process (GO:0019369) is a central lipid signaling pathway that generates diverse eicosanoids controlling inflammation, immunity, and cell death. Its dysregulation is implicated in cardiovascular disease, allergy, stroke, and cancer, making its enzymes important therapeutic targets [1,3,5,7,8]. Advances in CRISPR-based models and lipidomics are accelerating the discovery of causal mechanisms and novel drug candidates. EDITGENE provides the tools needed to dissect this pathway with precision, from knockout to knock-in models.
References
- 1. Chen Z et al.. 2026. Arachidonic acid fuels inflammation by unlocking macrophage protein phosphatase 5 after myocardial infarction.. Eur Heart J 47(4):503-518 PMID: 40905492
- 2. Fürstenberger G et al.. 2002. Arachidonate 8(S)-lipoxygenase.. Prostaglandins Other Lipid Mediat 68-69:235-43 PMID: 12432921
- 3. Xue P et al.. 2025. Arachidonic acid induces ferroptosis in hepatocellular carcinoma via the SIRT5-ACSL4/LPCAT3/ALOX15 axis, leading to lipid peroxidation and mitochondrial dysfunction.. Phytomedicine 148:157450 PMID: 41175589
- 4. Lončarić M et al.. 2021. Lipoxygenase Inhibition by Plant Extracts.. Biomolecules 11(2) PMID: 33503885
- 5. Lee YS et al.. 2015. Cross-platform meta-analysis of multiple gene expression profiles identifies novel expression signatures in acquired anthracycline-resistant breast cancer.. Oncol Rep 33(4):1985-93 PMID: 25695524
- 6. Romano M. 2006. Lipid mediators: lipoxin and aspirin-triggered 15-epi-lipoxins.. Inflamm Allergy Drug Targets 5(2):81-90 PMID: 16613567
- 7. Liu M et al.. 2015. The role of leukotrienes in allergic diseases.. Allergol Int 64(1):17-26 PMID: 25572555
- 8. Wang X et al.. 2025. The emerging role of 12/15-lipoxygenase in ischemic stroke.. Brain Res Bull 221:111194 PMID: 39788462
