```mermaid
flowchart TD
A["ACSL4<br/>Acyl-CoA Synthetase<br/>Long Chain Family 4"]
B["MIR130B3P<br/>MicroRNA 130b-3p"]
C["Ferroptosis<br/>Iron-dependent<br/>Cell Death"]
D["Lipid Peroxidation<br/>Oxidative Damage<br/>to Membrane Lipids"]
E["Arachidonic Acid<br/>Metabolism"]
F["Multiple Sclerosis<br/>MS"]
G["Amyotrophic Lateral<br/>Sclerosis<br/>ALS"]
H["Alzheimer's Disease<br/>AD"]
I["Neuroinflammation"]
J["Oxidative Stress<br/>ROS Generation"]
K["Membrane<br/>Integrity Loss"]
L["Neuronal Death"]
M["Iron Homeostasis<br/>Dysregulation"]
N["Phospholipid<br/>Biosynthesis"]
O["Therapeutic<br/>Intervention"]
B -->|"inhibits"| A
A -->|"promotes"| C
A -->|"promotes"| D
A -->|"regulates"| E
A -->|"activates"| N
C -->|"leads_to"| K
D -->|"causes"| J
E -->|"contributes_to"| D
N -->|"maintains"| K
J -->|"triggers"| C
M -->|"enhances"| C
K -->|"results_in"| L
C -->|"associated_with"| F
C -->|"associated_with"| G
A -->|"therapeutic_target"| O
O -->|"treats"| F
O -->|"treats"| G
A -->|"inhibits"| H
I -->|"promotes"| D
Acsl4 Gene Acyl Coa Synthetase Long Chain Family Member 4 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
<div class="infobox infobox-gene"> [@acsla]
<table> [@lipid]
<tr><th colspan="2" style="background:#f0f0f0;">ACSL4</th></tr> [@acslb]
<tr><td><b>Gene Symbol</b></td><td>ACSL4</td></tr>
<tr><td><b>Full Name</b></td><td>Acyl-CoA Synthetase Long Chain Family Member 4</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>Xq22.3</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>[2072](https://www.ncbi.nlm.nih.gov/gene/2072)</td></tr>
<tr><td><b>OMIM</b></td><td>[300402](https://www.omim.org/entry/300402)</td></tr>
<tr><td><b>Ensembl ID</b></td><td>ENSG00000068366</td></tr>
<tr><td><b>UniProt ID</b></td><td>[O60488](https://www.uniprot.org/uniprot/O60488)</td></tr>
<tr><td><b>Protein</b></td><td>ACSL4 (Long-chain acyl-CoA synthetase 4)</td></tr>
<tr><td><b>Associated Diseases</b></td><td>Amyotrophic Lateral Sclerosis (ALS), [Parkinson's Disease](/diseases/parkinsons-disease), [Alzheimer's Disease](/diseases/alzheimers-disease), X-linked intellectual disability, Ferroptosis</td></tr>
</table>
</div>
ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) encodes a member of the acyl-CoA synthetase family that catalyzes the conversion of long-chain fatty acids to acyl-CoA esters. ACSL4 is particularly important for ferroptosis sensitivity as it preferentially activates arachidonic acid and adrenic acid, which are substrates for lipid peroxidation during ferroptotic cell death.
ACSL4 catalyzes the following reaction:
What distinguishes ACSL4 from other ACSL family members:
ACSL4 is expressed in various neural cell types:
ACSL4 is a key determinant of ferroptosis sensitivity:
| Compound | Mechanism | Stage | Notes |
|----------|-----------|-------|-------|
| Rosiglitazone | PPARγ agonist, indirect | Approved (diabetes) | Off-target ACSL4 |
| Triacsin C | Direct ACSL inhibitor | Research | Not selective |
| Thiazolidinediones | Indirect inhibition | Approved | Pioglitazone |
Ferroptosis is an iron-dependent, non-apoptotic form of cell death characterized by lipid peroxidation[@acsl]. Unlike apoptosis or necrosis, ferroptosis is distinct in its morphology and biochemical mechanisms:
ACSL4 is essential for ferroptosis execution due to its unique substrate specificity[@acsl]:
Arachidonic Acid (20:4 n-6) → ACSL4 → Arachidonoyl-CoA → Phospholipid incorporation
↓
Lipid peroxidation (when Fe²⁺ present)
↓
Ferroptosis
The relationship between ACSL4 and GPX4 is central to ferroptosis regulation:
| GPX4 Status | ACSL4 Activity | Outcome |
|-------------|----------------|---------|
| Active | High | Ferroptosis resistance (low PUFA-PE) |
| Active | Low | Ferroptosis resistance |
| Inactive | High | Ferroptosis (high PUFA-PE, rapid peroxidation) |
| Inactive | Low | Variable (depends on other factors) |
ACSL4 is increasingly recognized in AD pathogenesis through multiple mechanisms[@acsla]:
| Strategy | Approach | Status |
|----------|----------|--------|
| ACSL4 inhibition | Reduce PUFA activation | Preclinical |
| Iron chelation | Deferoxamine, deferasirox | Mixed results |
| GPX4 activation | Ebselen, ferrostatin-1 | Research |
| Lipid diet modification | Reduce omega-6, increase omega-3 | Adjunct |
Motor neurons are particularly vulnerable to ferroptosis due to their high ACSL4 expression[@lipid]:
Dopaminergic neurons in the substantia nigra show particular vulnerability[@acsla]:
Understanding the interplay between ferroptosis and other cell death pathways is critical:
| Feature | Ferroptosis | Apoptosis |
|---------|-------------|-----------|
| Morphology | Mitochondrial shrinkage | Nuclear fragmentation |
| Membrane | Intact until late | Blebbing, fragmentation |
| Energy (ATP) | Required | Required |
| Caspases | Not involved | Activated |
| Iron | Essential | Not required |
| Lipid peroxidation | Central | Incidental |
| Compound | Specificity | IC50 | Stage | Notes |
|----------|-------------|------|-------|-------|
| Triacsin C | General ACSL | 0.5 μM | Research | Not selective for ACSL4 |
| Rosiglitazone | ACSL4 | 3-5 μM | Approved | PPARγ effects |
| Pioglitazone | ACSL4 | 5-10 μM | Approved | Better brain penetration |
| AVX-4800 | ACSL4 | 1.2 μM | Preclinical | More selective |
ACSL4 and related metabolites show promise as biomarkers:
| Marker | Sample | Utility | Status |
|--------|--------|---------|--------|
| ACSL4 expression | PBMCs | Disease progression | Research |
| Plasma 4-HNE | Plasma | Lipid peroxidation | Emerging |
| Phospholipid profile | Plasma/CSF | Ferroptosis risk | Experimental |
| Iron status | Serum | Vulnerability factor | Established |
ACSL4 serves as a critical determinant of ferroptosis susceptibility in neurons through its preferential activation of arachidonic acid and adrenic acid. The enzyme's activity directly influences cellular lipid composition, with PUFA-rich membranes becoming vulnerable to iron-catalyzed lipid peroxidation when antioxidant defenses (particularly GPX4) are compromised.
In neurodegenerative diseases including Alzheimer's disease, ALS, and Parkinson's disease, ACSL4-mediated ferroptosis contributes to the selective vulnerability of specific neuronal populations. Dopaminergic neurons, motor neurons, and hippocampal neurons all show high ACSL4 expression combined with iron accumulation and age-related antioxidant decline.
Therapeutic targeting of ACSL4, either directly or through upstream modulators like iron chelation and lipid modification, represents a promising approach to neuroprotection. However, the essential metabolic functions of ACSL4 necessitate careful consideration of potential side effects. Biomarker development for ferroptosis risk stratification and treatment response monitoring will be critical for clinical translation.
The study of Acsl4 Gene Acyl Coa Synthetase Long Chain Family Member 4 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) expression in the human brain has been characterized through the Allen Brain Atlas:
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
The following diagram shows the key molecular relationships involving ACSL4 Gene - Acyl-CoA Synthetase Long Chain Family Member 4 discovered through SciDEX knowledge graph analysis: