ACSL3

Summary

ACSL3 (acyl-CoA synthetase long chain family member 3, HGNC:3570) is a protein-coding gene on chromosome 2q36.1, encoding Fatty acid CoA ligase Acsl3 (O95573). Acyl-CoA synthetases (ACSL) activates long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. It is a selective cancer dependency (DepMap: 30.5% of cell lines).

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 is highly expressed in brain, and preferentially utilizes myristate, arachidonate, and eicosapentaenoate as substrates. The amino acid sequence of this isozyme is 92% identical to that of rat homolog. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 2181 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 98 total — 6 pathogenic
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 30.5% of screened cell lines
• MANE Select transcript: NM_004457

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3570
Approved symbol	ACSL3
Name	acyl-CoA synthetase long chain family member 3
Location	2q36.1
Locus type	gene with protein product
Status	Approved
Aliases	ACS3, PRO2194
Ensembl gene	ENSG00000123983
Ensembl biotype	protein_coding
OMIM	602371
Entrez	2181

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 31 protein_coding, 10 retained_intron, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000357430, ENST00000392066, ENST00000407441, ENST00000413316, ENST00000421680, ENST00000463813, ENST00000474422, ENST00000495541, ENST00000535678, ENST00000540115, ENST00000542810, ENST00000679514, ENST00000679541, ENST00000679545, ENST00000679546, ENST00000679558, ENST00000679932, ENST00000680100, ENST00000680147, ENST00000680251, ENST00000680382, ENST00000680395, ENST00000680420, ENST00000680424, ENST00000680475, ENST00000680525, ENST00000680684, ENST00000680736, ENST00000680921, ENST00000681009, ENST00000681017, ENST00000681292, ENST00000681326, ENST00000681383, ENST00000681697, ENST00000681906, ENST00000903381, ENST00000903382, ENST00000903383, ENST00000903384, ENST00000903385, ENST00000903386, ENST00000938744, ENST00000938745, ENST00000955376, ENST00000955377, ENST00000955378, ENST00000955379, ENST00000955380, ENST00000955381, ENST00000955382

RefSeq mRNA: 4 — MANE Select: NM_004457 NM_001354158, NM_001354159, NM_004457, NM_203372

CCDS: CCDS2455

Canonical transcript exons

ENST00000357430 — 17 exons

Exon	Start	End
ENSE00000786329	222919064	222919202
ENSE00000786330	222921280	222921430
ENSE00000786331	222922708	222922831
ENSE00000786332	222923078	222923149
ENSE00000786334	222927017	222927189
ENSE00000786335	222928862	222928936
ENSE00000922398	222908733	222909150
ENSE00000922400	222918046	222918155
ENSE00000922405	222924456	222924595
ENSE00000922408	222930621	222930812
ENSE00000922411	222941497	222944639
ENSE00001405381	222900674	222900780
ENSE00001407067	222887830	222887888
ENSE00001733043	222933166	222933280
ENSE00001902664	222861036	222861258
ENSE00003463885	222916319	222916496
ENSE00003467287	222934530	222934687

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 127.4037 / max 642.5973, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25632	120.1498	1825
25633	4.9567	1621
25631	1.2522	832
25638	0.4970	219
25636	0.2916	113
25634	0.2563	117

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.62	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.85	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.57	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.16	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.95	gold quality
cartilage tissue	UBERON:0002418	97.61	gold quality
frontal pole	UBERON:0002795	97.59	gold quality
postcentral gyrus	UBERON:0002581	97.43	gold quality
parietal lobe	UBERON:0001872	97.41	gold quality
substantia nigra pars compacta	UBERON:0001965	97.40	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.37	gold quality
occipital lobe	UBERON:0002021	97.35	gold quality
CA1 field of hippocampus	UBERON:0003881	97.34	gold quality
entorhinal cortex	UBERON:0002728	97.28	gold quality
lateral globus pallidus	UBERON:0002476	97.23	gold quality
primary visual cortex	UBERON:0002436	97.18	gold quality
orbitofrontal cortex	UBERON:0004167	96.93	gold quality
middle frontal gyrus	UBERON:0002702	96.82	gold quality
cranial nerve II	UBERON:0000941	96.81	gold quality
adrenal tissue	UBERON:0018303	96.77	gold quality
minor salivary gland	UBERON:0001830	96.76	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.74	gold quality
middle temporal gyrus	UBERON:0002771	96.73	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.73	gold quality
superior frontal gyrus	UBERON:0002661	96.68	gold quality
superior vestibular nucleus	UBERON:0007227	96.56	gold quality
pons	UBERON:0000988	96.47	gold quality
mouth mucosa	UBERON:0003729	96.45	gold quality
prefrontal cortex	UBERON:0000451	96.40	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.30	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	15.53
E-GEOD-137537	yes	6.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1H2, NR1H3, PPARD, RXRA

miRNA regulators (miRDB)

183 targeting ACSL3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-493-5P	99.96	72.47	2382

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 30.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• Sequence analysis of genomic clones demonstrates that the human ACS3 gene spans at least 80.6 kb and contains 17 exons. (PMID:11707336)
• Repression of FAS mRNA expression is the consequence of feedback inhibition of FAS expression by long chain fatty acyl-CoAs, which are formed by FACL3 during its upregulation by vitamin D3in prostate cancer cells. (PMID:15556626)
• Oncostatin M directly lowers the plasma triglycerides in hyperlipidemia by stimulating the transcription of ACSL3/5 in the liver. (PMID:17761945)
• Data suggest that endogenous FATP4 does not function to translocate fatty acids across the plasma membrane, but functions more as a very long-chain acyl-CoA synthetase. (PMID:17901542)
• Small interfering RNA targeting ACSL3 inhibits secretion of hepatitis c virus from human hepatoma-derived cells (PMID:18003621)
• Data suggest that methylated ACSL3 5’CpG islands in umbilical cord white blood cell DNA may be a surrogate endpoint for transplacental polycyclic aromatic hydrocarbon exposure and/or a potential biomarker for environmentally-related asthma. (PMID:19221603)
• Results suggest that liver X receptors play a regulatory role in fatty acid metabolism by direct regulation of ACSL3 in human placental trophoblast cells. (PMID:20219900)
• ACSL3 is a novel molecular target of PPARdelta in HepG2 cells; there is a regulatory mechanism for ACSL3 transcription in liver tissue (PMID:20308079)
• Results suggest that initiation of Golgi export of Lyn involves association of ACSL3 with the Lyn C-lobe, which is exposed to the molecular surface in an open conformation. (PMID:20605918)
• expression of ACSL3 was induced by endoplasmic reticulum stress (PMID:21328461)
• role of N-terminal region of acyl-CoA synthetase 3 in its function and localization on lipid droplets (PMID:22357706)
• activation of fatty acid import is linked to the up-regulation of cellular long chain acyl-CoA synthetase activity and identify the long chain acyl-CoA syntheatse3 (Acsl3) as a novel host factor required for polio replication. (PMID:23762027)
• The prominent expression of ACSL3 in VSMC. (PMID:23840832)
• ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer (PMID:27477280)
• ACLS4 and ACLS3 have roles in insulin secretion (PMID:28193492)
• Study shows that ACSL3 contributes to intratumoral steroidogenesis by modulating the steroidogenic genes and plays an important role in the growth of castration-resistant prostate cancer. (PMID:28771887)
• 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)
• Subcellular fractionation showed that at least 68% of ACSL3 remain at the ER even during extensive fatty acid supplementation. High resolution single molecule microscopy confirmed the abundance of cytoplasmic ACSL3 outside of LDs. (PMID:29526665)
• The ACSL3-LPIAT1 signaling drives prostaglandin synthesis in non-small cell lung cancer. (PMID:32034305)
• Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases. (PMID:32286604)
• Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non-small cell lung cancer. (PMID:33030783)
• Activation of MAT2A-ACSL3 pathway protects cells from ferroptosis in gastric cancer. (PMID:35182729)
• [Research advances on the role of ACSL3 in the atherosclerosis]. (PMID:37583046)
• ANKRD1 aggravates renal ischaemia-reperfusion injury via promoting TRIM25-mediated ubiquitination of ACSL3. (PMID:39285846)

Cross-species orthologs

27 orthologs

Organism	Symbol	Gene ID
danio_rerio	acsl3b	ENSDARG00000014674
mus_musculus	Acsl3	ENSMUSG00000032883
rattus_norvegicus	Acsl3	ENSRNOG00000014718
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): ACSL4 (ENSG00000068366), SLC27A5 (ENSG00000083807), ACSBG1 (ENSG00000103740), SLC27A6 (ENSG00000113396), SLC27A1 (ENSG00000130304), ACSBG2 (ENSG00000130377), SLC27A2 (ENSG00000140284), SLC27A3 (ENSG00000143554), ACSL1 (ENSG00000151726), ACSL6 (ENSG00000164398), SLC27A4 (ENSG00000167114), ACSL5 (ENSG00000197142)

Protein

Protein identifiers

Fatty acid CoA ligase Acsl3 — O95573 (reviewed: O95573)

Alternative names: Arachidonate–CoA ligase, Long-chain acyl-CoA synthetase 3, Long-chain-fatty-acid–CoA ligase 3, Medium-chain acyl-CoA ligase Acsl3

All UniProt accessions (10): A0A7P0T8L6, A0A7P0T905, A0A7P0TA76, A0A7P0TB52, A0A7P0TBB1, A0A7P0TBL9, C9JC11, O95573, F5GWH2, H7BYZ7

UniProt curated annotations — full annotation on UniProt →

Function. Acyl-CoA synthetases (ACSL) activates long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. Required for the incorporation of fatty acids into phosphatidylcholine, the major phospholipid located on the surface of VLDL (very low density lipoproteins). Has mainly an anabolic role in energy metabolism. Mediates hepatic lipogenesis. Preferentially uses myristate, laurate, arachidonate and eicosapentaenoate as substrates. Both isoforms exhibit the same level of activity.

Subcellular location. Mitochondrion outer membrane. Peroxisome membrane. Microsome membrane. Endoplasmic reticulum membrane.

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

RefSeq proteins (4): NP_001341087, NP_001341088, NP_004448, NP_976251 (=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

Pfam: PF00501

Enzyme classification (BRENDA):

• 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)

48 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	0.0065–9.7	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
LINOLENATE	0.0016–0.0073	2
OCTADECANOATE	0.061–0.072	2
PALMITOLEATE	0.0015–0.002	2

Catalyzed reactions (Rhea), 12 shown:

• 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)
• (9Z)-octadecenoate + ATP + CoA = (9Z)-octadecenoyl-CoA + AMP + diphosphate (RHEA:33607)
• octadecanoate + ATP + CoA = octadecanoyl-CoA + AMP + diphosphate (RHEA:33615)
• tetradecanoate + ATP + CoA = tetradecanoyl-CoA + AMP + diphosphate (RHEA:33619)
• dodecanoate + ATP + CoA = dodecanoyl-CoA + AMP + diphosphate (RHEA:33623)
• (9Z)-hexadecenoate + ATP + CoA = (9Z)-hexadecenoyl-CoA + AMP + diphosphate (RHEA:33647)
• (9Z,12Z)-octadecadienoate + ATP + CoA = (9Z,12Z)-octadecadienoyl-CoA + AMP + diphosphate (RHEA:33651)
• (E)-hexadec-2-enoate + ATP + CoA = (2E)-hexadecenoyl-CoA + AMP + diphosphate (RHEA:36139)
• a fatty acid + ATP + CoA = a fatty acyl-CoA + AMP + diphosphate (RHEA:38883)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + ATP + CoA = (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA + AMP + diphosphate (RHEA:44932)

UniProt features (6 total): chain 1, transmembrane region 1, topological domain 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95573-F1	88.79	0.63

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 (1): 683

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

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

MSigDB gene sets: 415 (showing top): REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, MODULE_52, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, PAX4_01, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_PHOSPHATIDYLCHOLINE_BIOSYNTHETIC_PROCESS, GOZGIT_ESR1_TARGETS_DN, GCM_ZNF198, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (11): long-chain fatty acid metabolic process (GO:0001676), fatty acid metabolic process (GO:0006631), neuron differentiation (GO:0030182), very-low-density lipoprotein particle assembly (GO:0034379), long-chain fatty-acyl-CoA metabolic process (GO:0035336), long-chain fatty-acyl-CoA biosynthetic process (GO:0035338), positive regulation of Golgi to plasma membrane protein transport (GO:0042998), long-chain fatty acid import into cell (GO:0044539), positive regulation of secretion (GO:0051047), positive regulation of phosphatidylcholine biosynthetic process (GO:2001247), lipid metabolic process (GO:0006629)

GO Molecular Function (11): long-chain fatty acid-CoA ligase activity (GO:0004467), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein domain specific binding (GO:0019904), medium-chain fatty acid-CoA ligase activity (GO:0031956), arachidonate-CoA ligase activity (GO:0047676), palmitoyl-CoA ligase activity (GO:0090433), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874), fatty acid-CoA ligase activity (GO:0120515)

GO Cellular Component (11): mitochondrial outer membrane (GO:0005741), peroxisomal membrane (GO:0005778), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), lipid droplet (GO:0005811), plasma membrane (GO:0005886), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), mitochondrion (GO:0005739), peroxisome (GO:0005777)

Reactome top-level categories

Rollup of top-7 pathways:

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

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
intracellular membrane-bounded organelle	3
fatty acid-CoA ligase activity	2
long-chain fatty acid-CoA ligase activity	2
endomembrane system	2
cellular anatomical structure	2
fatty acid metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
cell differentiation	1
generation of neurons	1
plasma lipoprotein particle assembly	1
fatty-acyl-CoA metabolic process	1
long-chain fatty-acyl-CoA metabolic process	1
fatty-acyl-CoA biosynthetic process	1
regulation of Golgi to plasma membrane protein transport	1
Golgi to plasma membrane protein transport	1
positive regulation of protein transport	1
positive regulation of protein localization to plasma membrane	1
long-chain fatty acid transport	1
import into cell	1
lipid import into cell	1
secretion	1
regulation of secretion	1
positive regulation of transport	1
phosphatidylcholine biosynthetic process	1
positive regulation of phospholipid biosynthetic process	1
regulation of phosphatidylcholine biosynthetic process	1
primary metabolic process	1
long-chain fatty acid metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
fatty acid ligase activity	1
CoA-ligase activity	1

Protein interactions and networks

STRING

2586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACSL3	AASDH	Q4L235	902
ACSL3	CPT1A	P50416	874
ACSL3	DGAT1	O75907	867
ACSL3	ACACA	Q13085	748
ACSL3	ABCD1	P33897	722
ACSL3	ABCD3	P28288	690
ACSL3	SLC27A2	O14975	673
ACSL3	ACACB	O00763	657
ACSL3	CD36	P16671	653
ACSL3	HMGCS2	P54868	645
ACSL3	ACLY	P53396	640
ACSL3	SCARB2	Q14108	637
ACSL3	SCARB1	Q8WTV0	636
ACSL3	FASN	P49327	632
ACSL3	COASY	Q13057	631

IntAct

183 interactions, top by confidence:

A	B	Type	Score
WDR19	TULP3	psi-mi:“MI:0914”(association)	0.860
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
rep	AGPS	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
IFT140	ACSL3	psi-mi:“MI:0914”(association)	0.510
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
STX17	ACSL3	psi-mi:“MI:0915”(physical association)	0.470

BioGRID (365): ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Proximity Label-MS), ACSL3 (Proximity Label-MS), ACSL3 (Proximity Label-MS), ACSL3 (Proximity Label-MS), ACSL3 (Proximity Label-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS), ACSL3 (Affinity Capture-MS)

ESM2 similar proteins: A0A2H5AIX5, A0A2H5AIY4, A0A6B9HER0, C8VTR6, I3PB37, M4IQR7, M4IQS1, M4IRL6, M4ISH0, O24145, O24146, O24540, O95573, P08659, P0C5B6, P13129, P14912, P14913, P17814, P31684, P31685, P31686, P31687, P41636, Q01158, Q0DV32, Q10S72, Q17577, Q26304, Q27757, Q3E6Y4, Q42524, Q54P77, Q54P78, Q54P79, Q5BA81, Q5R668, Q67W82, Q84P21, Q84P23

Diamond homologs: A4TS06, A5JTM6, A6UED8, A6WXV8, A7FNG1, A8G8G7, B2HHZ8, B5ZV36, C3MAS0, E9Q9W4, M4IRL9, O35488, O53551, O95573, P97524, P97849, Q07VK4, Q0S4D7, Q0VSR6, Q1C0N0, Q1CE37, Q21LV0, Q3ZKN0, Q4LDG0, Q5R668, Q60714, Q66FM8, Q6FLU2, Q6PCB7, Q7MGU3, Q7TWC5, Q8D1G8, Q8DCZ9, Q8Z1R0, Q8ZKF6, Q92KX2, Q9CMW1, Q9Y2P5, A0A0H3C605, A0R3D6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 189 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by ERBB2 ECD mutants	5	25.6×	2e-04
GRB2 events in ERBB2 signaling	5	24.2×	2e-04
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	19.8×	3e-04
SHC1 events in ERBB2 signaling	5	18.2×	4e-04
Signaling by ERBB2 TMD/JMD mutants	5	18.2×	4e-04
Signaling by ERBB2 KD Mutants	5	16.1×	7e-04
Downstream signal transduction	5	14.5×	9e-04
FCERI mediated MAPK activation	5	13.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of MAPK cascade	12	5.9×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — AML.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	62
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
146029	GRCh38/hg38 2q36.1-36.2(chr2:221663502-224426183)x1	Pathogenic
1526954	GRCh37/hg19 2q36.1(chr2:222828685-224451613)	Pathogenic
1526955	GRCh37/hg19 2q36.1-37.1(chr2:223378640-232061074)	Pathogenic
1703585	GRCh37/hg19 2q36.1-36.2(chr2:222902251-226084516)	Pathogenic
3148939	GRCh37/hg19 2q35-37.3(chr2:216815496-242782258)x3	Pathogenic
635897	Single allele	Pathogenic

SpliceAI

2907 predictions. Top by Δscore:

Variant	Effect	Δscore
2:222861256:GCG:G	donor_gain	1.0000
2:222916314:ATCAG:A	acceptor_gain	1.0000
2:222916316:CAG:C	acceptor_loss	1.0000
2:222916317:A:AG	acceptor_gain	1.0000
2:222916317:A:T	acceptor_loss	1.0000
2:222916317:AG:A	acceptor_gain	1.0000
2:222916318:G:GA	acceptor_gain	1.0000
2:222916318:GG:G	acceptor_gain	1.0000
2:222916318:GGTT:G	acceptor_gain	1.0000
2:222916471:G:GT	donor_gain	1.0000
2:222916476:GTTT:G	donor_gain	1.0000
2:222916477:TTTT:T	donor_gain	1.0000
2:222916495:GC:G	donor_gain	1.0000
2:222918044:A:AG	acceptor_gain	1.0000
2:222918045:G:GG	acceptor_gain	1.0000
2:222918045:GTT:G	acceptor_gain	1.0000
2:222918151:TGAAG:T	donor_loss	1.0000
2:222918152:GAAGG:G	donor_loss	1.0000
2:222918153:AAG:A	donor_loss	1.0000
2:222918154:AG:A	donor_loss	1.0000
2:222918155:GGTG:G	donor_loss	1.0000
2:222918156:GTG:G	donor_loss	1.0000
2:222918157:T:G	donor_loss	1.0000
2:222919056:A:AG	acceptor_gain	1.0000
2:222919057:T:G	acceptor_gain	1.0000
2:222919062:A:AG	acceptor_gain	1.0000
2:222919062:A:T	acceptor_loss	1.0000
2:222919062:AG:A	acceptor_gain	1.0000
2:222919063:G:A	acceptor_loss	1.0000
2:222919063:G:GC	acceptor_gain	1.0000

AlphaMissense

4718 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:222924469:G:C	R389P	1.000
2:222930770:G:C	D564H	1.000
2:222930771:A:G	D564G	1.000
2:222933169:G:C	R579P	1.000
2:222933181:T:C	L583P	1.000
2:222933186:A:G	K585E	1.000
2:222933190:T:C	L586P	1.000
2:222933208:T:A	V592D	1.000
2:222941550:T:A	W687R	1.000
2:222941550:T:C	W687R	1.000
2:222909094:C:A	R108S	0.999
2:222922800:G:A	G350D	0.999
2:222923145:T:A	V383D	0.999
2:222923148:C:A	P384Q	0.999
2:222923148:C:G	P384R	0.999
2:222924551:A:C	K416N	0.999
2:222924551:A:T	K416N	0.999
2:222927049:G:A	G442E	0.999
2:222927151:G:A	G476E	0.999
2:222928889:G:A	G498E	0.999
2:222928919:T:C	L508S	0.999
2:222928927:T:A	W511R	0.999
2:222928927:T:C	W511R	0.999
2:222930656:G:C	G526R	0.999
2:222930657:G:A	G526D	0.999
2:222930657:G:T	G526V	0.999
2:222930767:G:T	G563W	0.999
2:222930768:G:A	G563E	0.999
2:222930768:G:T	G563V	0.999
2:222930771:A:C	D564A	0.999

dbSNP variants (sampled 300 via entrez): RS1000016553 (2:222898368 C>T), RS1000024308 (2:222862087 A>C,G), RS1000031438 (2:222889163 C>A), RS1000071562 (2:222870660 A>T), RS1000129745 (2:222928313 A>G,T), RS1000140044 (2:222885115 T>C), RS1000324369 (2:222909952 A>G), RS1000329082 (2:222917129 C>G,T), RS1000337965 (2:222864986 T>C), RS1000409145 (2:222868225 G>T), RS1000442059 (2:222940215 G>A,C), RS1000442870 (2:222910215 A>G), RS1000449560 (2:222884906 C>T), RS1000544988 (2:222910141 T>G), RS1000556224 (2:222922592 C>G,T)

Disease associations

OMIM: gene MIM:602371 | disease phenotypes: MIM:189800, MIM:193500

GenCC curated gene-disease

Mondo (3): preeclampsia (MONDO:0005081), Waardenburg syndrome type 1 (MONDO:0008670), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Preeclampsia (Orphanet:275555), Waardenburg syndrome type 1 (Orphanet:894)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003124_27	Mild influenza (H1N1) infection	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001488	influenza A (H1N1)

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D011225	Pre-Eclampsia	C12.050.703.395.249

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4680023 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 5 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.24	Kd	5733	nM	CHEMBL3752910
5.24	ED50	5733	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 14 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147790: Binding affinity to human ACSL3 incubated for 45 mins by Kinobead based pull down assay	kd	5.7331	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	6
Benzo(a)pyrene	decreases expression, decreases methylation	5
bisphenol A	affects expression, decreases methylation, increases expression	3
sodium arsenite	affects expression, decreases expression	3
Acetaminophen	affects expression, increases expression	3
Air Pollutants	affects cotreatment, decreases expression, increases abundance	3
Tetrachlorodibenzodioxin	affects expression, decreases expression, affects cotreatment	3
Metribolone	affects binding, increases reaction, increases expression	3
Cyclosporine	affects expression, increases expression	3
methylselenic acid	affects expression, decreases expression	2
trichostatin A	affects expression, increases expression	2
Testosterone	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Genistein	decreases expression, increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
graphene oxide	increases expression	1
dicrotophos	decreases expression	1
daidzein	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
senecionine	decreases expression	1
daidzin	decreases expression, affects cotreatment	1
mono-(2-ethylhexyl)phthalate	increases expression	1
cobaltous chloride	increases expression	1
cupric oxide	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
genistin	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	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
CHEMBL4678697	Binding	Inhibition of recombinant human ACSL3 assessed as reduction in acetyl-coA prodution incubated for 90 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

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1IW	Abcam HeLa ACSL3 KO	Cancer cell line	Female
CVCL_DX21	HAP1 ACSL3 (-) ACSL4 (-)	Cancer cell line	Male
CVCL_XK98	HAP1 ACSL3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00117546	PHASE4	UNKNOWN	Cardiovascular and Autonomic Reactivity in Women With a History of Pre-eclampsia
NCT00567957	PHASE4	UNKNOWN	Remifentanil for General Anesthesia in Preeclamptics
NCT01030627	PHASE4	COMPLETED	Treatment Approaches to Preeclampsia
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01361425	PHASE4	UNKNOWN	Anti-Hypertensive Treatment In Stable Pregnant Women With Severe Pre-Eclampsia (Metildopape)
NCT01729468	PHASE4	COMPLETED	Prevention of Pre-eclampsia and SGA by Low-Dose Aspirin in Nulliparous Women With Abnormal First-trimester Uterine Artery Dopplers
NCT01761916	PHASE4	COMPLETED	Clonidine Versus Captopril for Treatment of Postpartum Very High Blood Pressure
NCT01912677	PHASE4	COMPLETED	Oral Antihypertensive Regimens for Management of Hypertension in Pregnancy
NCT02025426	PHASE4	TERMINATED	Phenylephrine Versus Ephedrine in Pre-eclampsia
NCT02091401	PHASE4	COMPLETED	A Trial Comparing Treatment With the Springfusor Infusion Pump to the IV Magnesium Sulfate Regimen
NCT02163655	PHASE4	COMPLETED	Diuretics for Postpartum High Blood Pressure in Preeclampsia
NCT02338687	PHASE4	COMPLETED	Low Dose Calcium to Prevent Preeclampsia
NCT02396030	PHASE4	TERMINATED	Different Schemes of Magnesium Sulfate for Preeclampsia
NCT02531490	PHASE4	UNKNOWN	Early Vascular Adjustments During Hypertensive Pregnancy
NCT02699827	PHASE4	COMPLETED	Adding MgSO4 to Epidural Levobupivacaine in CS for Patients With Preeclampsia
NCT02835339	PHASE4	COMPLETED	Magnesium Sulfate in Obese Preeclamptics
NCT02891174	PHASE4	COMPLETED	The Effect of Ibuprofen on Post-partum Blood Pressure in Women With Hypertensive Disorders of Pregnancy
NCT02911701	PHASE4	COMPLETED	Effect of Acetaminophen on Postpartum Blood Pressure Control in Preeclampsia With Severe Features
NCT03171480	PHASE4	COMPLETED	Use of Nitrous Oxide Donor for Labor Induction in Women With PreEclampsia
NCT03233880	PHASE4	UNKNOWN	Impact of Antichlamydial Treatment on the Rate of Preeclampsia
NCT03237000	PHASE4	UNKNOWN	Effect of Administering Intravenous Magnesium Sulfate on Fetal Cardiotocography and Neonatal Outcome in Preeclamptic Patients
NCT03506724	PHASE4	COMPLETED	Response to Anti-hypertensives in Pregnant and Postpartum Patients
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT03735433	PHASE4	TERMINATED	The Effect of Two Aspirin Dosing Strategies for Obese Women at High Risk for Preeclampsia
NCT03824119	PHASE4	UNKNOWN	Postpartum NSAIDS and Maternal Hypertension
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT04077853	PHASE4	COMPLETED	Progesterone in Expectantly Managed Early-onset Preeclampsia
NCT04158830	PHASE4	WITHDRAWN	Aspirin (ASA) Therapy and Preeclampsia Prevention
NCT04424693	PHASE4	UNKNOWN	Comparing the Incidence of Preeclampsia Between Pregnant Women Receiving Tdap Vaccinations at Week 28 or at Week 36
NCT04631627	PHASE4	UNKNOWN	Early Prediction and Randomised Prevention of Preeclampsia With Low Dose Aspirin in Chinese Cohort
NCT04656665	PHASE4	UNKNOWN	The Effectiveness of Aspirin on Preventing Pre-eclampsia
NCT04797949	PHASE4	WITHDRAWN	Adherence to Universal Aspirin Compared to Screening Indicated Aspirin for Prevention of Preeclampsia
NCT04908982	PHASE4	UNKNOWN	Aspirin for the Prevention of Preeclampsia in Women With Stage 1 Hypertension
NCT05221164	PHASE4	UNKNOWN	162 mg of Aspirin for Prevention of Preeclampsia
NCT05294952	PHASE4	UNKNOWN	co Ihibtory Receptor in Preeclampsia
NCT05514847	PHASE4	ACTIVE_NOT_RECRUITING	Low Dose Aspirin for Preterm Preeclampsia Preventionmg/day Dose in High-risk Patients
NCT05586373	PHASE4	COMPLETED	Ibuprofen vs Dipyrone After C-section in Preeclampsia
NCT06069102	PHASE4	COMPLETED	Optimal Blood Pressure Treatment Thresholds Postpartum
NCT06107335	PHASE4	NOT_YET_RECRUITING	Effect of Albumin Versus Routine Care on Hemodynamic Response and Stability in Patients With Preeclampsia Guided by a Non-invasive Hemodynamic Monitoring System During Cesarean Delivery With Spinal Anesthesia
NCT06281665	PHASE4	RECRUITING	Treatment With Aspirin After Preeclampsia: TAP Trial