ACSL4

Summary

ACSL4 (acyl-CoA synthetase long chain family member 4, HGNC:3571) is a protein-coding gene on chromosome Xq23, encoding Long-chain-fatty-acid–CoA ligase 4 (O60488). Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation.

The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the cognitive disability or Alport syndrome. Alternative splicing of this gene generates multiple transcript variants.

Source: NCBI Gene 2182 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-syndromic X-linked intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 390 total — 26 pathogenic, 11 likely-pathogenic (top 8% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈3% of expected missense variation)
• GTEx eGene: eQTL in 23 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 30
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001318510
• Interaction hub: 2,362 STRING partners (top 5% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3571
Approved symbol	ACSL4
Name	acyl-CoA synthetase long chain family member 4
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	ACS4, LACS4
Ensembl gene	ENSG00000068366
Ensembl biotype	protein_coding
OMIM	300157
Entrez	2182

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 30 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000672401

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 3, TSL 4: 2, TSL 5: 3

ENST00000672401, ENST00000340800, ENST00000348502, ENST00000439581, ENST00000469796, ENST00000502391, ENST00000504383, ENST00000505075, ENST00000505855, ENST00000508092, ENST00000514500, ENST00000671846, ENST00000672282, ENST00000673016, ENST00000682031, ENST00000683559, ENST00000684030, ENST00000684414, ENST00000851255, ENST00000851256, ENST00000851257, ENST00000851258, ENST00000915898, ENST00000915899, ENST00000915900, ENST00000953314, ENST00000953315, ENST00000953316, ENST00000953317, ENST00000953318, ENST00000953319, ENST00001010756, ENST00001116338, ENST00001116339, ENST00001116340, ENST00001116341, ENST00001116342, ENST00001116343

RefSeq mRNA: 11 — MANE Select: NM_001318510 NM_001318509, NM_001318510, NM_001437245, NM_001437247, NM_001437248, NM_001437250, NM_001437251, NM_001437252, NM_001437253, NM_004458, NM_022977

CCDS: CCDS14548, CCDS14549

Canonical transcript exons

ENST00000672401 — 16 exons

Exon	Start	End
ENSE00000674526	109669034	109669173
ENSE00000674527	109668101	109668273
ENSE00000674528	109665420	109665494
ENSE00000674532	109659354	109659511
ENSE00000895425	109677988	109678111
ENSE00000895428	109678265	109678415
ENSE00000895431	109680998	109681136
ENSE00000895440	109681266	109681375
ENSE00000895444	109682719	109682896
ENSE00000979252	109674402	109674473
ENSE00000979255	109663211	109663402
ENSE00001159638	109696144	109696196
ENSE00001699022	109661531	109661645
ENSE00002053298	109683136	109683375
ENSE00003892017	109641335	109644186
ENSE00003893060	109733139	109733257

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 77.1970 / max 6809.8709, expressed in 1746 samples.

Highest expression (Bgee): adrenal tissue, monocyte, mononuclear cell, colonic epithelium, leukocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ACSL4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 24 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adrenal Gland	eqtl	3.3e-10	+0.24	X:109782672:G:A
Liver	eqtl	8.1e-09	-0.37	X:109792251:C:T
Cells EBV-transformed lymphocytes	sqtl	4.4e-06	+1.60	X:109453927:G:T
Muscle Skeletal	eqtl	7.9e-05	-0.12	X:109699236:G:T
Whole Blood	eqtl	1.3e-04	-0.06	X:109699236:G:T
Cells EBV-transformed lymphocytes	eqtl	1.7e-04	-0.32	X:109461296:G:T
Thyroid	eqtl	2.6e-04	-0.26	X:109636296:G:A
Artery Tibial	eqtl	4.2e-04	+0.09	X:109860735:G:GC
Brain Hippocampus	eqtl	5.6e-04	-0.45	X:109302100:G:A
Pancreas	eqtl	6.8e-04	+0.32	X:109741251:C:G
Skin Sun Exposed Lower leg	eqtl	8.3e-04	-0.11	X:109699236:G:T
Adipose Subcutaneous	eqtl	4.0e-03	-0.11	X:109740240:C:T
Cells Cultured fibroblasts	eqtl	5.2e-03	+0.22	X:109426475:G:A
Artery Aorta	eqtl	5.5e-03	+0.10	X:109849028:A:AT
Esophagus Mucosa	eqtl	5.9e-03	-0.11	X:109699236:G:T
Lung	eqtl	8.1e-03	+0.18	X:109655725:T:C
Brain Spinal cord cervical c-1	eqtl	9.7e-03	-0.74	X:109340720:A:G
Nerve Tibial	eqtl	1.8e-02	-0.07	X:110429730:T:C
Brain Frontal Cortex BA9	eqtl	2.1e-02	+0.06	X:109719433:A:G
Brain Putamen basal ganglia	eqtl	2.3e-02	+0.68	X:109247274:G:A

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
200131	53.8063	1727
200130	11.4606	1626
200132	10.9589	1646
200135	0.2600	23
200134	0.2580	101
200133	0.2306	95
200136	0.1386	18
200137	0.0840	10

Top tissues by expression

showing 100 of 289 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	97.41	gold quality
monocyte	CL:0000576	94.73	gold quality
mononuclear cell	CL:0000842	94.25	gold quality
colonic epithelium	UBERON:0000397	94.08	gold quality
leukocyte	CL:0000738	93.91	gold quality
cortical plate	UBERON:0005343	93.60	gold quality
calcaneal tendon	UBERON:0003701	93.00	gold quality
right adrenal gland	UBERON:0001233	92.98	gold quality
adrenal gland	UBERON:0002369	92.63	gold quality
left adrenal gland	UBERON:0001234	92.60	gold quality
right adrenal gland cortex	UBERON:0035827	92.40	gold quality
islet of Langerhans	UBERON:0000006	92.37	gold quality
gall bladder	UBERON:0002110	92.18	gold quality
left adrenal gland cortex	UBERON:0035825	92.14	gold quality
adrenal cortex	UBERON:0001235	91.76	gold quality
right lung	UBERON:0002167	91.21	gold quality
omental fat pad	UBERON:0010414	90.91	gold quality
peritoneum	UBERON:0002358	90.86	gold quality
upper lobe of left lung	UBERON:0008952	90.86	gold quality
upper lobe of lung	UBERON:0008948	90.79	gold quality
stromal cell of endometrium	CL:0002255	90.42	gold quality
lower lobe of lung	UBERON:0008949	90.31	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.94	gold quality
vermiform appendix	UBERON:0001154	89.08	gold quality
pericardium	UBERON:0002407	88.95	gold quality
prefrontal cortex	UBERON:0000451	88.76	gold quality
gastrocnemius	UBERON:0001388	88.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.32	gold quality
left coronary artery	UBERON:0001626	88.26	gold quality
metanephros cortex	UBERON:0010533	88.15	gold quality
endometrium	UBERON:0001295	87.90	gold quality
right atrium auricular region	UBERON:0006631	87.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.70	gold quality
descending thoracic aorta	UBERON:0002345	87.69	gold quality
muscle of leg	UBERON:0001383	87.58	gold quality
coronary artery	UBERON:0001621	87.46	gold quality
superficial temporal artery	UBERON:0001614	87.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.24	gold quality
popliteal artery	UBERON:0002250	87.15	gold quality
tibial artery	UBERON:0007610	87.15	gold quality
right coronary artery	UBERON:0001625	87.14	gold quality
aorta	UBERON:0000947	87.03	gold quality
lung	UBERON:0002048	87.03	gold quality
ascending aorta	UBERON:0001496	86.99	gold quality
thoracic aorta	UBERON:0001515	86.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.81	gold quality
lymph node	UBERON:0000029	86.71	gold quality
adipose tissue	UBERON:0001013	86.71	gold quality
blood	UBERON:0000178	86.63	gold quality
caecum	UBERON:0001153	86.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.01	gold quality
mucosa of stomach	UBERON:0001199	85.72	gold quality
left uterine tube	UBERON:0001303	85.68	gold quality
cardiac atrium	UBERON:0002081	85.67	gold quality
adult mammalian kidney	UBERON:0000082	85.66	gold quality
spinal cord	UBERON:0002240	85.62	gold quality
connective tissue	UBERON:0002384	85.58	gold quality
rectum	UBERON:0001052	85.49	gold quality
smooth muscle tissue	UBERON:0001135	85.45	gold quality
corpus callosum	UBERON:0002336	85.02	gold quality
heart	UBERON:0000948	85.00	gold quality
heart left ventricle	UBERON:0002084	84.98	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.83	gold quality
endocervix	UBERON:0000458	84.70	gold quality
cingulate cortex	UBERON:0003027	84.49	gold quality
ovary	UBERON:0000992	84.41	gold quality
cardiac ventricle	UBERON:0002082	84.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.31	gold quality
anterior cingulate cortex	UBERON:0009835	84.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.26	gold quality
lower esophagus	UBERON:0013473	84.24	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.24	gold quality
germinal epithelium of ovary	UBERON:0001304	84.18	gold quality
left ovary	UBERON:0002119	84.18	gold quality
pancreas	UBERON:0001264	84.12	gold quality
right ovary	UBERON:0002118	84.05	gold quality
hypothalamus	UBERON:0001898	84.01	gold quality
amygdala	UBERON:0001876	83.58	gold quality
right testis	UBERON:0004534	83.52	gold quality
tonsil	UBERON:0002372	83.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.44	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.41	gold quality
uterus	UBERON:0000995	83.40	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.40	gold quality
testis	UBERON:0000473	83.26	gold quality
kidney	UBERON:0002113	83.07	gold quality
esophagus	UBERON:0001043	83.02	gold quality
granulocyte	CL:0000094	82.94	gold quality
body of stomach	UBERON:0001161	82.77	gold quality
stomach	UBERON:0000945	82.74	gold quality
ganglionic eminence	UBERON:0004023	82.67	gold quality
right frontal lobe	UBERON:0002810	82.64	gold quality
female reproductive system	UBERON:0000474	82.63	gold quality
spleen	UBERON:0002106	82.60	gold quality
minor salivary gland	UBERON:0001830	82.58	gold quality
body of uterus	UBERON:0009853	82.58	gold quality
ectocervix	UBERON:0012249	82.53	gold quality
nucleus accumbens	UBERON:0001882	82.20	gold quality
neocortex	UBERON:0001950	82.04	gold quality
left testis	UBERON:0004533	81.95	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	743.86
E-CURD-119	yes	48.57
E-CURD-88	yes	25.52
E-ANND-3	yes	18.90
E-GEOD-130148	yes	14.10
E-CURD-112	yes	13.85
E-MTAB-9067	yes	13.28
E-CURD-122	yes	11.32
E-MTAB-9801	yes	7.58
E-HCAD-10	yes	6.81
E-GEOD-135922	yes	6.50
E-CURD-46	yes	5.75
E-MTAB-5061	yes	4.04
E-MTAB-6142	no	138.84

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Urinary bladder	tissue	62.0	medium
Locus coeruleus	tissue	49.9
Cervix	tissue	43.6
Hippocampal formation	tissue	42.5
Kidney	tissue	42.0	medium
Frontal cortex	tissue	41.7
Cerebral cortex	tissue	40.6	high
Motor cortex	tissue	40.6
Somatosensory cortex	tissue	39.9
Adipose tissue	tissue	38.3	medium
Retrosplenial and cingulate cortex	tissue	38.2
Prefrontal cortex	tissue	38.1
Pons	tissue	38.0
Temporal cortex	tissue	37.6
Occipital cortex	tissue	37.5
Hippocampus	tissue	36.6	high
Entorhinal cortex	tissue	36.1
Lung	tissue	35.4	high
Adrenal gland	tissue	34.9	medium
Thalamus	tissue	34.6
Appendix	tissue	34.5	low
Hypothalamus	tissue	33.6
Putamen	tissue	33.1
Retrosplenial cortex	tissue	32.2
Septum	tissue	31.8
Postcentral gyrus	tissue	31.5
Midbrain	tissue	31.4
Basal ganglia	tissue	30.7	medium
Substantia nigra	tissue	30.2
Insular cortex	tissue	29.9
Amygdala	tissue	27.8
Ventral forebrain	tissue	27.6
Heart muscle	tissue	26.9	low
Gallbladder	tissue	25.8	medium
Olfactory bulb	tissue	25.7
Nucleus accumbens	tissue	25.3
Choroid plexus	tissue	23.5
Periaqueductal gray	tissue	23.5
Testis	tissue	23.3	low
Caudate putamen	tissue	23.1
Superior colliculi	tissue	23.0
Lymph node	tissue	20.7	low
Retina	tissue	20.7
Ovary	tissue	20.0	not detected
Smooth muscle	tissue	19.9	low
Medulla oblongata	tissue	19.4
Placenta	tissue	19.4	medium
Spleen	tissue	19.4	low
Parathyroid gland	tissue	18.4	medium
Thymus	tissue	18.3
Stomach 1	tissue	17.6	medium
Endometrium 1	tissue	17.4	low
Thyroid gland	tissue	17.2	medium
Spinal cord	tissue	16.4
Tonsil	tissue	16.0	medium
Tongue	tissue	15.8
Cerebellum	tissue	15.7	medium
Esophagus	tissue	14.6	low
Seminal vesicle	tissue	14.0	low
Duodenum	tissue	13.8	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Lateral hypothalamic area (55.0), Orbitofrontal gyrus, anterior (47.4), Median raphe nucleus (44.5), Ventral hippocampus (42.5), Hippocampus, CA1 (41.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, MYC, SP1, TCF3

miRNA regulators (miRDB)

Targeting ACSL4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 261 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996

Functional genomics

Regional missense constraint (gnomAD)

ENST00000672401 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈3% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
X:109,644,032–109,678,034	175 / 275.8	0.63	no
X:109,678,035–109,678,105	1 / 16.8	0.06	yes (p 1.2e-04)
X:109,678,106–109,683,363	157 / 201.1	0.78	no
ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma. (PMID:11731423)
• FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation (PMID:11889465)
• FACL4 is highly expressed in hippocampal and cerebellar neurons and may have a role in X linked mental retardation. (PMID:12525535)
• Overexpression of Fatty acid-CoA ligase 4 is associated with human hepatocellular carcinoma (PMID:12824887)
• FACL4 is involved in the hepatocellular carcinoma tumorigenesis and both cAMP and p38 MAPK pathways are associated with the regulation of FACL4 (PMID:15849811)
• Disruption of DMD and the absence of ACSL4 in a patient are responsible for neuromuscular disease and cognitive impairment. (PMID:16276108)
• FACL4 affects HCC cell growth and suggest that modulation of FACL4 expression/activity is an approach for treatment of HCC. (PMID:17934335)
• FACL4 might play a role in the growth of hepatic cancer cells. (PMID:18059177)
• No association between polymorphisms in the FACL4 (fatty acid-CoA ligase 4) gene and nonspecific mental retardation in Qin-Ba mountain region of China. (PMID:18614287)
• The common SNP (C to T substitution) in the first intron of the FACL4 gene is associated with altered Fatty Acid composition of plasma phosphatidylcholines in patients with metabolic syndrome . (PMID:19346733)
• ACSL4 can substitute the functions of dAcsl(l(2)44DEa in organismal viability, lipid storage and the neural wiring in visual center. (PMID:19617635)
• This study found no significant relationship between FACL4 and cognitive function. (PMID:20452052)
• Data suggest that the development of combinatory therapies that profit from the ACSL4, lipooxygenase and COX-2 synergistic action may allow for lower medication doses and avoidance of side effects. (PMID:21085606)
• CSL4 modulates PGE release from human erial smooth muscle cells. (PMID:21242590)
• A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33. (PMID:21384559)
• the involvement of SHP2 activity in the regulation of the expression of the fatty acid-metabolizing enzyme ACSL4 (PMID:21903867)
• The functional interaction between Acyl-CoA synthetase 4, 5-lipooxygenase and cyclooxygenase-2 controls tumor growth. (PMID:22808264)
• ACSL4 can serve as both a biomarker for, and mediator of, an aggressive breast cancer phenotype. (PMID:24155918)
• conclude that in our model system exogenous fatty acids are channeled preferentially towards phosphatidylinositol by ACSL4 overexpression (PMID:24201376)
• MiR-205 down-regulates ACSL4 through targeting its 3’UTR in hepatoma cells. (PMID:24576478)
• studies have identified a novel substrate-induced posttranslational regulatory mechanism by which AA downregulates ACSL4 protein expression in hepatic cells. (PMID:24879802)
• Upregulation of ACSL4 is responsible for the increase in triacylglycerol species containing long polyunsaturated fatty acids during activation of hepatic stellate cells. (PMID:25500141)
• Report PPARdelta-mediated regulatory mechanism for ACSL4 expression in liver tissue and cultured hepatic cells. (PMID:25645621)
• In vitro analysis showed that a recombinant COX-2 enzyme more effectively metabolized 5(S)-HETE to 5-11-diHETE compared to COX-1 enzyme. (PMID:26282205)
• we demonstrate that ACSL4 can be considered a novel activator of the mTOR pathway (PMID:26536660)
• Suggest role for ACSL4 expression in development of castration-resistant prostate cancer. (PMID:26636648)
• ACSL4 plays a tumor-suppressive role in gastric cancer. (PMID:26949059)
• ACSL4 is not only a sensitive monitor of ferroptosis, but also an important contributor of ferroptosis. (PMID:27565726)
• Data show that ELOVL7, SOCS3, ACSL4 and CLU were upregulated while PRKAR1A and ABCG1 were downregulated in the phlegm-dampness group. (PMID:27928700)
• ACLS4 and ACLS3 have roles in insulin secretion (PMID:28193492)
• Silencing of ACSL4 eliminated the 17beta-estradiol-induced increase in AA and EPA uptake. (PMID:28334272)
• These results suggest that ACSL1, ACSL4 and ACSL5 expression is regulated by ER signaling pathways and ACSL5 is a potential novel biomarker for predicting prognosis of breast cancer patients. (PMID:28498416)
• Study demonstrated that ACSL4 was overexpressed in HCC. (PMID:28887439)
• ACSL3 distribution closely overlapped with proteins involved in trafficking from the trans-Golgi network and endosomes. In contrast, the ACSL4 localisation pattern more closely followed that of calnexin which is an endoplasmic reticulum resident chaperone. (PMID:29450800)
• The regulatory network among peroxisomal ABCD2:ACSL4:VLCFA serves as a novel regulator of cartilage homeostasis, and these data may provide novel insights into the role of peroxisomal fatty acid metabolism in pathogenesis of human osteoarthritis (OA). (PMID:30264402)
• ACSL4 role in the drug resistance in breast cancer cell lines. (PMID:30414939)
• the A20-ACSL4 axis plays important roles in erastin-induced endothelial ferroptosis. (PMID:31160087)
• Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells. (PMID:31311992)
• LncRNA NEAT1 promotes docetaxel resistance in prostate cancer by regulating ACSL4 via sponging miR-34a-5p and miR-204-5p. (PMID:31672604)
• Study shows that the expression of ACSL4 is downregulated in human glioma tissues and cells and demonstrates that ACSL4 protects glioma cells and exerts antiproliferative effects by activating a ferroptosis pathway. These results also highlight the pivotal role of ferroptosis regulation by ACSL4 in its protective effects on glioma. (PMID:31789401)

Cross-species orthologs

28 orthologs

Organism	Symbol	Gene ID
danio_rerio	acsl4a	ENSDARG00000004078
danio_rerio	acsl4b	ENSDARG00000010752
mus_musculus	Acsl4	ENSMUSG00000031278
rattus_norvegicus	Acsl4	ENSRNOG00000019180
drosophila_melanogaster	bgm	FBGN0027348
drosophila_melanogaster	pdgy	FBGN0027601
drosophila_melanogaster	CG8834	FBGN0033733
drosophila_melanogaster	CG17999	FBGN0034552
drosophila_melanogaster	CG9993	FBGN0034553
drosophila_melanogaster	Fatp3	FBGN0034999
drosophila_melanogaster	CG4563	FBGN0035006
drosophila_melanogaster	CG5568	FBGN0035641
drosophila_melanogaster	CG18586	FBGN0035642
drosophila_melanogaster	CG4830	FBGN0037996
drosophila_melanogaster	Acsx1L	FBGN0038730
drosophila_melanogaster	Acsx1R	FBGN0038731
drosophila_melanogaster	Acsx2	FBGN0038732
drosophila_melanogaster	Acsx3	FBGN0038733
drosophila_melanogaster	Acsx4	FBGN0038734
drosophila_melanogaster	Fatp2	FBGN0265187
drosophila_melanogaster	Fatp1	FBGN0267828
drosophila_melanogaster	hll	FBGN0286723
caenorhabditis_elegans		WBGENE00007082
caenorhabditis_elegans		WBGENE00008669
caenorhabditis_elegans		WBGENE00009218
caenorhabditis_elegans		WBGENE00011173
caenorhabditis_elegans		WBGENE00019920
caenorhabditis_elegans		WBGENE00022849

Paralogs (12): SLC27A5 (ENSG00000083807), ACSBG1 (ENSG00000103740), SLC27A6 (ENSG00000113396), ACSL3 (ENSG00000123983), SLC27A1 (ENSG00000130304), ACSBG2 (ENSG00000130377), SLC27A2 (ENSG00000140284), SLC27A3 (ENSG00000143554), ACSL1 (ENSG00000151726), ACSL6 (ENSG00000164398), SLC27A4 (ENSG00000167114), ACSL5 (ENSG00000197142)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1354713) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 17 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body length	2
abnormal tibia morphology	1
abnormal female reproductive system morphology	1
dilated uterus	1
decreased body weight	1
reduced female fertility	1
decreased litter size	1
increased corpora lutea number	1
decreased heart weight	1
thrombocytopenia	1
decreased lean body mass	1
enlarged ovary	1
abnormal endometrium morphology	1
uterus cyst	1
abnormal uterus physiology	1
increased prostaglandin level	1
preweaning lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Streptococcus pneumoniae ATCC 700669	B8ZQ14	100.0%	Diamond
Streptococcus pneumoniae Taiwan19F-14	C1CU95	100.0%	Diamond
Pongo abelii	Q5R668	99.7%	Diamond
Arabidopsis thaliana	Q9FFE6	92.0%	Diamond
Cavia porcellus	Q9JID6	88.7%	Diamond
Streptococcus equi subsp. equi 4047	C0MBD6	82.8%	Diamond
Saccharomyces cerevisiae S288C	P39002	78.5%	Diamond
Coprinopsis cinerea okayama7#130	A8NVB7	78.1%	Diamond
Humulus lupulus	M4ISH2	69.3%	Diamond
Fusarium pseudograminearum CS3096	K3VAW3	63.7%	Diamond
Fusarium graminearum PH-1	I1S3K7	58.8%	Diamond
Dictyostelium discoideum	Q55DR6	45.8%	Diamond
Lactococcus lactis subsp. lactis Il1403	Q9CG49	44.0%	Diamond
Schizosaccharomyces pombe 972h-	O60135	43.3%	Diamond
Aspergillus fumigatus Af293	Q4WR82	39.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
KCNE5	protein-coding	23630
MIR652	ncRNA	724022
TMEM164	protein-coding	84187
MIR3978	ncRNA	100616491
NXT2	protein-coding	55916
SNORD96B	snoRNA	692226
AMMECR1	protein-coding	9949

Protein

Protein identifiers

Long-chain-fatty-acid–CoA ligase 4 — O60488 (reviewed: O60488)

Alternative names: Arachidonate–CoA ligase, Long-chain acyl-CoA synthetase 4

All UniProt accessions (5): A0A804HI36, O60488, D6RDA8, D6RF95, H0Y9A0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation. Preferentially activates arachidonate and eicosapentaenoate as substrates. Preferentially activates 8,9-EET > 14,15-EET > 5,6-EET > 11,12-EET. Modulates glucose-stimulated insulin secretion by regulating the levels of unesterified EETs. Modulates prostaglandin E2 secretion. Acts as an activator of ferroptosis by activating polyunsaturated fatty acids, especially arachidonate and adrenate, to their active form, generating the primary lipid-peroxidation substrates that contribute to ferroptosis.

Subcellular location. Mitochondrion outer membrane. Endoplasmic reticulum membrane. Cell membrane.

Post-translational modifications. Phosphorylation at Thr-328 by isoform Beta-II of PRKCB promotes activation and lipid peroxidation, thereby inducing ferroptosis. Phosphorylation at Thr-679 by PCK2 promotes ferroptosis.

Disease relevance. Intellectual developmental disorder, X-linked 63 (XLID63) [MIM:300387] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked intellectual disability, while syndromic forms presents with associated physical, neurological and/or psychiatric manifestations. The disease is caused by variants affecting the gene represented in this entry. AMME complex (ATS-MR) [MIM:300194] An X-linked contiguous gene deletion syndrome characterized by glomerulonephritis, sensorineural hearing loss, intellectual disability, midface hypoplasia and elliptocytosis. The gene represented in this entry may be involved in disease pathogenesis.

Activity regulation. Both triacsin C and rosiglitazone inhibit arachidonoyl-CoA ligase activity. Specifically inhibited by thiazolidinediones, preventing ferroptosis.

Similarity. Belongs to the ATP-dependent AMP-binding enzyme family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60488-1	Long, V2	yes
O60488-2	Short, V1

RefSeq proteins (11): NP_001305438, NP_001305439, NP_001424174, NP_001424176, NP_001424177, NP_001424179, NP_001424180, NP_001424181, NP_001424182, NP_004449, NP_075266 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000873	AMP-dep_synth/lig_dom	Domain
IPR020845	AMP-binding_CS	Conserved_site
IPR042099	ANL_N_sf	Homologous_superfamily
IPR045851	AMP-b_sf	Homologous_superfamily

Pfam: PF00501

Enzyme classification (BRENDA)

• EC 6.2.1.15 — arachidonate-CoA ligase (BRENDA: 5 organisms, 10 substrates, 16 inhibitors, 20 Km, 0 kcat entries)
• EC 6.2.1.3 — long-chain-fatty-acid-CoA ligase (BRENDA: 48 organisms, 205 substrates, 100 inhibitors, 159 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

52 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.025–12.21	28
COA	0.0005–4.7	21
PALMITATE	0.0002–6	19
OLEATE	0.0014–3	9
ARACHIDONATE	0.0058–0.0793	7
ATP	0.029–2.39	6
COA	0.005–0.15	6
ARACHIDONATE	0.0065–9.7	6
STEARATE	0.0002–0.12	6
DECANOATE	0.004–0.0083	4
LAURATE	0.0005–0.002	4
LINOLEATE	0.0022–0.041	4
MYRISTATE	0.0002–0.0024	4
OCTANOATE	0.0007–0.0408	4
LAURIC ACID	0.0017–0.0163	3

Catalyzed reactions (Rhea)

• a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl-CoA + AMP + diphosphate (RHEA:15421)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + ATP + CoA = (5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:19713)
• hexadecanoate + ATP + CoA = hexadecanoyl-CoA + AMP + diphosphate (RHEA:30751)
• (E)-hexadec-2-enoate + ATP + CoA = (2E)-hexadecenoyl-CoA + AMP + diphosphate (RHEA:36139)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + ATP + CoA = (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA + AMP + diphosphate (RHEA:44932)
• 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoate + ATP + CoA = 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoyl-CoA + AMP + diphosphate (RHEA:52008)
• 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoate + ATP + CoA = 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoyl-CoA + AMP + diphosphate (RHEA:52012)
• 14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoate + ATP + CoA = 14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoyl-CoA + AMP + diphosphate (RHEA:52016)
• 5,6-epoxy-(8Z,11Z,14Z)-eicosatrienoate + ATP + CoA = 5,6-epoxy-(8Z,11Z,14Z)-eicosatrienoyl-CoA + AMP + diphosphate (RHEA:52088)
• 5-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + ATP + CoA = 5-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:52108)
• 12-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + ATP + CoA = 12-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:52112)
• 15-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + ATP + CoA = 15-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:52116)

UniProt features (13 total): modified residue 3, sequence variant 3, mutagenesis site 2, chain 1, transmembrane region 1, sequence conflict 1, topological domain 1, splice variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60488-F1	90.46	0.66

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Ligase, Metabolic proteins, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Mental and behavioural disorders

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; mitochondria

Antibody reliability (HPA): IH supported · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3)

Type	Positions
Phosphothreonine	328, 679
Phosphoserine	447

Mutagenesis-validated functional residues (2)

Position	Phenotype
328	abolished phosphorylation by isoform beta-ii of prkcb, preventing ferroptosis.
679	abolished phosphorylation by pck2, preventing ferroptosis.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 9; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-434313	Intracellular metabolism of fatty acids regulates insulin secretion	curated
R-HSA-75876	Synthesis of very long-chain fatty acyl-CoAs	curated
R-HSA-8978868	Fatty acid metabolism	—
R-HSA-75105	Fatty acyl-CoA biosynthesis	—
R-HSA-400451	Free fatty acids regulate insulin secretion	—
R-HSA-163685	Integration of energy metabolism	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-422356	Regulation of insulin secretion	—

MSigDB gene sets: 527 (showing top): AHRARNT_01, GGGACCA_MIR133A_MIR133B, RNGTGGGC_UNKNOWN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_ICOSANOID_SECRETION, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PROSTAGLANDIN_SECRETION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, RORA1_01, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (12): long-chain fatty acid metabolic process (GO:0001676), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633), lipid biosynthetic process (GO:0008610), neuron differentiation (GO:0030182), positive regulation of cell growth (GO:0030307), positive regulation of insulin secretion (GO:0032024), negative regulation of prostaglandin secretion (GO:0032307), long-chain fatty-acyl-CoA metabolic process (GO:0035336), long-chain fatty-acyl-CoA biosynthetic process (GO:0035338), positive regulation of ferroptosis (GO:0160020)

GO Molecular Function (7): long-chain fatty acid-CoA ligase activity (GO:0004467), ATP binding (GO:0005524), very long-chain fatty acid-CoA ligase activity (GO:0031957), arachidonate-CoA ligase activity (GO:0047676), palmitoyl-CoA ligase activity (GO:0090433), nucleotide binding (GO:0000166), ligase activity (GO:0016874)

GO Cellular Component (10): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), extracellular exosome (GO:0070062)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Metabolism	2
Free fatty acids regulate insulin secretion	1
Fatty acyl-CoA biosynthesis	1
Regulation of insulin secretion	1
Integration of energy metabolism	1
Fatty acid metabolism	1
Metabolism of lipids	1

GO top-level categories

51 GO namespaces:

Category	Terms
fatty acid metabolic process	2
lipid metabolic process	2
fatty acid-CoA ligase activity	2
long-chain fatty acid-CoA ligase activity	2
cellular anatomical structure	2
cytoplasm	2
intracellular membrane-bounded organelle	2
primary metabolic process	1
monocarboxylic acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
biosynthetic process	1
cell differentiation	1
generation of neurons	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
negative regulation of icosanoid secretion	1
regulation of prostaglandin secretion	1
prostaglandin secretion	1
negative regulation of secretion by cell	1
fatty-acyl-CoA metabolic process	1
long-chain fatty-acyl-CoA metabolic process	1
fatty-acyl-CoA biosynthetic process	1
positive regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
long-chain fatty acid metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular anatomical structure	1
mitochondrial membrane	1
organelle outer membrane	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
organelle membrane contact site	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 18 of 29 annotations. The rest are phylogenetic / computational / electronic (IEA).

18 experimentally-supported GO terms:

GO term	NS	Evidence
lipid biosynthetic process	BP	direct assay
lipid metabolic process	BP	direct assay
long-chain fatty acid metabolic process	BP	direct assay
negative regulation of prostaglandin secretion	BP	direct assay
positive regulation of cell growth	BP	direct assay
positive regulation of ferroptosis	BP	direct assay
cytoplasm	CC	direct assay
endoplasmic reticulum	CC	direct assay
extracellular exosome	CC	high-throughput assay
lipid droplet	CC	direct assay
membrane	CC	high-throughput assay
mitochondria-associated endoplasmic reticulum membrane contact site	CC	direct assay
mitochondrial outer membrane	CC	direct assay
mitochondrion	CC	high-throughput
plasma membrane	CC	direct assay
arachidonate-CoA ligase activity	MF	direct assay
long-chain fatty acid-CoA ligase activity	MF	direct assay
very long-chain fatty acid-CoA ligase activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 2,362 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACSL4	AMMECR1	Q9Y4X0	921
ACSL4	LPCAT3	Q6P1A2	904
ACSL4	GPX4	P36969	886
ACSL4	DGAT1	O75907	809
ACSL4	SLC27A2	O14975	806
ACSL4	COL4A5	P29400	788
ACSL4	SLC7A11	Q9UPY5	781
ACSL4	AIFM2	Q9BRQ8	758
ACSL4	KCNE5	Q9UJ90	748
ACSL4	FTH1	P02794	741
ACSL4	AASDH	Q4L235	734
ACSL4	TFRC	P02786	728
ACSL4	NCOA4	Q13772	723
ACSL4	ASCL4	Q6XD76	723
ACSL4	SLC3A2	P08195	708

IntAct

Human interaction partners of ACSL4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

22 partners by confidence:

Partner	Interaction type	MIscore	Records
CCT8L2	association	0.530	1
H2BC9	physical association	0.400	1
YWHAZ	physical association	0.400	1
DSE	physical association	0.370	1
ACSL3	association	0.350	1
ACTRT2	association	0.350	1
ALOX5	association	0.350	1
ASGR2	association	0.350	1
CHCHD10	association	0.350	1
CHCHD2	association	0.350	1
EID3	association	0.350	1
FOXJ1	association	0.350	1
HSD11B1	association	0.350	1
MTMR14	association	0.350	1
NAGA	association	0.350	1
NPRL3	association	0.350	1
PE25	association	0.350	1
QTRT1	association	0.350	1
RSPH14	association	0.350	1
SPART	association	0.350	1
TBC1D22A	association	0.350	1
TMEM150A	association	0.350	1

BioGRID (284 interactions; top human partners by supporting records): FBXO10 (Affinity Capture-Western; 6 records), ACSL3 (Affinity Capture-MS; 5 records), CARM1 (Affinity Capture-MS; 4 records), CDK1 (Affinity Capture-Western; 4 records), HTATIP2 (Affinity Capture-Western; 4 records), ARIH1 (Affinity Capture-MS; 3 records), CBL (Affinity Capture-MS; 3 records), CBLL1 (Affinity Capture-MS; 3 records), EID3 (Affinity Capture-MS; 3 records), GNAT2 (Affinity Capture-MS; 3 records), HAT1 (Affinity Capture-MS; 3 records), PARK2 (Affinity Capture-MS; 3 records), PJA1 (Affinity Capture-MS; 3 records), RBBP6 (Affinity Capture-MS; 3 records), RNF25 (Affinity Capture-MS; 3 records)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
ACSL4	up-regulates	Ferroptosis
miR-3173-5p	“down-regulates quantity by repression”	ACSL4	“translation regulation”

Disease & clinical

Genetic variants

Variant evidence for ACSL4: 390 ClinVar records (37 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

390 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	11
Uncertain significance	142
Likely benign	39
Benign	13

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 37 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
281523	NM_001318510.2(ACSL4):c.845_846del (p.His282fs)	Pathogenic	criteria provided, single submitter	1
1675197	NM_001318510.2(ACSL4):c.802del (p.Leu268fs)	Pathogenic	criteria provided, single submitter	1
3342837	NM_001318510.2(ACSL4):c.727C>T (p.Arg243Ter)	Pathogenic	criteria provided, single submitter	1
3382992	NM_001318510.2(ACSL4):c.1235dup (p.Met413fs)	Pathogenic	criteria provided, single submitter	1
11566	NM_001318510.2(ACSL4):c.1001C>T (p.Pro334Leu)	Likely pathogenic	criteria provided, single submitter	2
625210	NM_001318510.2(ACSL4):c.1712T>G (p.Val571Gly)	Likely pathogenic	criteria provided, single submitter	1
1691846	NM_001318510.2(ACSL4):c.1653_1654insT (p.Lys552Ter)	Likely pathogenic	criteria provided, single submitter	1
1709879	NM_001318510.2(ACSL4):c.1072_1073del (p.Leu358fs)	Likely pathogenic	criteria provided, single submitter	1
3362695	NM_001318510.2(ACSL4):c.1315+1G>A	Likely pathogenic	criteria provided, single submitter	1
3364111	NM_001318510.2(ACSL4):c.1855dup (p.Met619fs)	Likely pathogenic	criteria provided, single submitter	1
3777030	NM_001318510.2(ACSL4):c.629_630insC (p.Glu210fs)	Likely pathogenic	criteria provided, single submitter	1
58661	GRCh38/hg38 Xq21.1-25(chrX:81261589-126519353)x3	Pathogenic	criteria provided, single submitter	1
58667	GRCh38/hg38 Xq23(chrX:109690866-110088881)x2	Pathogenic	criteria provided, single submitter	1
221776	GRCh37/hg19 Xq22.1-24(chrX:99931059-120328627)x1	Pathogenic	criteria provided, single submitter	1
548953	GRCh37/hg19 Xq23(chrX:108919564-108929311)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ACSL4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 1,001):

Position(s)	Effect	Δscore	Sites
X:109659352–109659353	donor_loss	1.0000	5
X:109659512–109659513	acceptor_loss	1.0000	6
X:109659522	acceptor_gain	1.0000
X:109661529–109661530	donor_loss	1.0000	5
X:109661646–109661647	acceptor_loss	1.0000	5
X:109663209–109663210	donor_loss	1.0000	4
X:109663403	acceptor_gain	1.0000
X:109663403	acceptor_loss	1.0000
X:109663412	acceptor_gain	1.0000	2
X:109665418–109665419	donor_loss	1.0000	5

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000678

Disease associations

OMIM: gene MIM:300157 | disease phenotypes: MIM:300387

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
intellectual disability, X-linked 63	Strong	X-linked	4
non-syndromic X-linked intellectual disability	Moderate	X-linked	2

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Definitive	XL

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
DDG2P	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green

Mondo (3): intellectual disability, X-linked 63 (MONDO:0010313), intellectual disability (MONDO:0001071), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (2): X-linked non-syndromic intellectual disability (Orphanet:777), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

30 phenotypes (HPO-id order):

HPO	Term
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000365	Hearing impairment
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000545	Myopia
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000944	Abnormal metaphysis morphology
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001347	Hyperreflexia
HP:0001423	X-linked dominant inheritance
HP:0001595	Abnormal hair morphology
HP:0001643	Patent ductus arteriosus
HP:0001646	Abnormal aortic valve morphology
HP:0002907	Microscopic hematuria
HP:0004445	Elliptocytosis
HP:0005280	Depressed nasal bridge
HP:0010864	Severe intellectual disability
HP:0011069	Supernumerary tooth
HP:0011463	Childhood onset
HP:0012471	Thick vermilion border
HP:0100820	Glomerulopathy

GWAS associations

1 associations:

Study	Trait	p-value
GCST90002395_86	Mean platelet volume	2e-10

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564522	Mental Retardation, X-Linked 63 *(supp.)*
C564490	Mental Retardation, X-Linked Nonsyndromic *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4680022 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

3 measured of 5 human assays (5 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM
CHEMBL4761388	IC50	69000 nM
CHEMBL4776019	IC50	114000 nM

CTD chemical–gene interactions

123 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ferrostatin-1	affects reaction, increases expression, decreases reaction, increases abundance, decreases expression	9
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	5
Valproic Acid	affects reaction, decreases expression, increases expression, decreases methylation, increases methylation	5
sodium arsenite	decreases reaction, affects cotreatment, increases abundance, affects reaction, decreases expression (+1 more)	4
bisphenol A	increases expression, affects expression, decreases expression	3
deoxynivalenol	increases expression, decreases expression	3
methylmercuric chloride	decreases expression	2
trichostatin A	affects cotreatment, increases expression	2
cobaltous chloride	affects cotreatment, increases expression, decreases expression	2
Resveratrol	affects cotreatment, increases expression	2
Caffeine	affects phosphorylation, decreases expression	2
Chloroquine	decreases reaction, increases abundance, increases expression	2
Deferoxamine	decreases reaction, increases expression	2
Nickel	increases expression	2
Tretinoin	affects cotreatment, decreases expression, increases expression	2
Oleic Acid	affects cotreatment, increases expression, decreases expression	2
Particulate Matter	decreases reaction, increases expression, increases reaction	2
aristolochic acid I	decreases expression	1
aurantio-obtusin	increases expression	1
bisphenol F	increases expression	1
beauvericin	decreases expression, affects cotreatment	1
2,4,6-tribromophenol	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	decreases reaction, increases expression	1
lead acetate	decreases expression	1
nuciferine	decreases reaction, increases expression	1
leonurine	decreases reaction, increases expression	1
arsenite	affects binding, decreases reaction	1
Firemaster BP-6	decreases reaction, increases expression, affects reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4678695	Binding	Inhibition of recombinant human ACSL4 assessed as reduction in acetyl-coA prodution incubated for 120 mins in presence of Coenzyme A, ATP and MgCl2 by MALDI-TOF MS analysis	Discovery of a benzimidazole series as the first highly potent and selective ACSL1 inhibitors. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B5JF	HAP1 ACSL4 (-) 2	Cancer cell line	Male
CVCL_D7FT	Abcam A-431 ACSL4 KO	Cancer cell line	Female
CVCL_DX21	HAP1 ACSL3 (-) ACSL4 (-)	Cancer cell line	Male
CVCL_E0X3	Ubigene L-02 ACSL4 KO	Cancer cell line	Female
CVCL_F1LR	HyCyte A-549 KO-hACSL4	Cancer cell line	Male
CVCL_F1TU	HyCyte THP-1 KO-hACSL4	Cancer cell line	Male
CVCL_XK99	HAP1 ACSL4 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00391261	Phase 4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	Phase 4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	Phase 4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	Phase 4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	Phase 4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	Phase 4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	Phase 4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	Phase 4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	Phase 4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	Phase 4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	Phase 4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	Phase 4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	Phase 4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	Phase 4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	Phase 4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	Phase 4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	Phase 4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	Phase 4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	Phase 4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	Phase 4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	Phase 4	RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT07770152	Phase 4	NOT_YET_RECRUITING	Semaglutide in Youth With Autism Spectrum Disorder
NCT01302964	Phase 3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	Phase 3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	Phase 3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	Phase 3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	Phase 3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	Phase 3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	Phase 3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	Phase 3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	Phase 3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	Phase 3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	Phase 3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	Phase 3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	Phase 3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	Phase 3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	Phase 3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	Phase 3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	Phase 3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	Phase 3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	Phase 3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder
NCT06333964	Phase 3	COMPLETED	A Study to Evaluate the Efficacy and Safety of AST-001 in ASD Children
NCT07257939	Phase 3	NOT_YET_RECRUITING	NTI164 in Autism Spectrum Disorder
NCT07655115	Phase 3	RECRUITING	Single Dose Double-blind, Placebo-controlled Cross-over (SDDBPCCO) Shiftability Study, Will be Followed by a 10-week Open-label Study With Arbaclofen (4 Weeks of Titration and Then 6 Weeks of Active/Stable Treatment). The Effects of Arbaclofen on Target EEG and ERG Metrics Will be Associated With th
NCT00251303	Phase 2	COMPLETED	Riluzole to Treat Child and Adolescent Obsessive-Compulsive Disorder With or Without Autism Spectrum Disorders
NCT00614198	Phase 2	COMPLETED	ScanBrit Dietary Intervention in Autism
NCT00619190	Phase 2	COMPLETED	Study of Aripiprazole to Treat Children and Adolescents With Autism
NCT00709202	Phase 2	COMPLETED	Efficacy and Tolerability Study of Betahistine to Ameliorate Antipsychotic Associated Weight Gain
NCT00846547	Phase 2	COMPLETED	Open-Label Study of the Safety and Tolerability of STX209 in Subjects With Autism Spectrum Disorders
NCT01064973	Phase 2	TERMINATED	An Open Label Extension Study of STX209 in Subjects With Autism Spectrum Disorders
NCT01170325	Phase 2	WITHDRAWN	A Study of Divalproex Sodium in Children With ASD and Epileptiform EEG
NCT01205282	Phase 2	COMPLETED	Dose Finding Study of Pioglitazone in Children With Autism Spectrum Disorders (ASD) (PIO)
NCT01248130	Phase 2	TERMINATED	Omega-3 Fatty Acids Monotherapy in Children and Adolescents With Autism Spectrum Disorders
NCT01248728	Phase 2	COMPLETED	Omega-3 Fatty Acids For Treatment Of Young Children With Autism (OMG)
NCT01256060	Phase 2	COMPLETED	Intranasal Oxytocin for the Treatment of Children and Adolescents With ASD (OXY)
NCT01288716	Phase 2	COMPLETED	Study of Arbaclofen for the Treatment of Social Withdrawal in Subjects With Autism Spectrum Disorders
NCT01300923	Phase 2	COMPLETED	Acamprosate in Youth With Fragile X Syndrome
NCT01366859	Phase 2	COMPLETED	Nutritional Intervention in Children With Autism Using Whey Protein (Immunocal): Impact on Core Areas of Behavior
NCT01372449	Phase 2	COMPLETED	A Multi-site Double-blind Placebo-controlled Trial of Memantine Versus Placebo in Children With Autism (MEM)
NCT01395953	Phase 2	WITHDRAWN	Double-blind Trial of Buspirone for the Treatment of Anxiety in Youth With Autism Spectrum Disorders

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ACSL4 across ~30M SureChEMBL compounds — explore on Sugi Predict.