CASP4

gene

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Also known as ICE(rel)IIICH-2TX

Summary

CASP4 (caspase 4, HGNC:1505) is a protein-coding gene on chromosome 11q22.3, encoding Caspase-4 (P49662). Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis.

This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain and a large and small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This caspase is able to cleave and activate its own precursor protein, as well as caspase 1 precursor. When overexpressed, this gene induces cell apoptosis. Alternative splicing results in transcript variants encoding distinct isoforms.

Source: NCBI Gene 837 — RefSeq curated summary.

At a glance

GWAS associations: 1
Clinical variants (ClinVar): 63 total
Druggable target: yes
MANE Select transcript: NM_001225

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1505
Approved symbol	CASP4
Name	caspase 4
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	ICE(rel)II, ICH-2, TX
Ensembl gene	ENSG00000196954
Ensembl biotype	protein_coding
OMIM	602664
Entrez	837

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 retained_intron, 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000393150, ENST00000417440, ENST00000444739, ENST00000524843, ENST00000525116, ENST00000529183, ENST00000529565, ENST00000530309, ENST00000531333, ENST00000531546, ENST00000533252, ENST00000533730, ENST00000534356

RefSeq mRNA: 2 — MANE Select: NM_001225 NM_001225, NM_033306

CCDS: CCDS41704, CCDS8327

Canonical transcript exons

ENST00000444739 — 9 exons

Exon	Start	End
ENSE00002296249	104968519	104968574
ENSE00002489770	104942866	104942973
ENSE00003502150	104948533	104948676
ENSE00003641514	104950925	104951098
ENSE00003651686	104951896	104952005
ENSE00003664006	104954747	104955001
ENSE00003671188	104944748	104944851
ENSE00003675649	104947083	104947192
ENSE00003684019	104949543	104949777

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 99.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.5651 / max 719.0503, expressed in 1576 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122075	39.3779	1576
122073	0.1536	47
122074	0.0337	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.01	gold quality
leukocyte	CL:0000738	98.69	gold quality
mononuclear cell	CL:0000842	98.68	gold quality
granulocyte	CL:0000094	98.56	gold quality
blood	UBERON:0000178	97.45	gold quality
calcaneal tendon	UBERON:0003701	97.05	gold quality
upper lobe of left lung	UBERON:0008952	96.87	gold quality
body of pancreas	UBERON:0001150	96.75	gold quality
gall bladder	UBERON:0002110	96.75	gold quality
right lung	UBERON:0002167	96.69	gold quality
spleen	UBERON:0002106	96.32	gold quality
colonic epithelium	UBERON:0000397	96.16	gold quality
upper lobe of lung	UBERON:0008948	96.15	gold quality
omental fat pad	UBERON:0010414	96.11	gold quality
peritoneum	UBERON:0002358	96.06	gold quality
minor salivary gland	UBERON:0001830	95.89	gold quality
skin of abdomen	UBERON:0001416	95.61	gold quality
esophagus mucosa	UBERON:0002469	95.45	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.34	gold quality
pancreas	UBERON:0001264	95.33	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.23	gold quality
bone marrow cell	CL:0002092	95.09	gold quality
islet of Langerhans	UBERON:0000006	95.07	gold quality
skin of leg	UBERON:0001511	94.90	gold quality
descending thoracic aorta	UBERON:0002345	94.78	gold quality
right coronary artery	UBERON:0001625	94.69	gold quality
tendon	UBERON:0000043	94.58	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.53	gold quality
mouth mucosa	UBERON:0003729	94.40	gold quality
stromal cell of endometrium	CL:0002255	94.36	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	19.03
E-ENAD-27	yes	6.09
E-MTAB-6379	no	1836.11
E-GEOD-110499	no	753.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, DDIT3, ESR1, IRF6, LEF1, NFKB, PARP1, STAT1, TSHZ3

miRNA regulators (miRDB)

8 targeting CASP4, 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-4492	99.87	68.25	3611
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-6837-3P	98.42	66.71	1149
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-3907	96.76	65.04	662
HSA-MIR-4268	94.45	64.09	819

Literature-anchored findings (GeneRIF, showing 40)

Caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer’s disease. (PMID:15123740)
resistance of pro-interleukin-18 to processing by caspase 1 in ovarian tumors (PMID:15326478)
caspase-12 and caspase-4 are not required for the induction of ER stress-induced apoptosis and that caspase-4-like activity is not always associated with an initiating event. (PMID:15975932)
Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. (PMID:16920334)
the familial Alzheimer’s disease-linked presenilin 1 mutation accelerates the cleavage of caspase-4 under the endoplasmic reticulum stress (PMID:17942194)
These results demonstrate that induction of GADD153/CHOP plays a pivotal role in mechanism of ER stress-induced cell death in SH-SY5Y cells, on the other hand, cleavage of pro-caspase-4 by activation of calpain play a crucial role in SK-N-SH cells. (PMID:18029041)
TRAF6-caspase-4 interaction, triggered by LPS, leads to NF-kappaB-dependent transcriptional up-regulation and secretion of important cytokines and chemokines in innate immune signaling in human monocytic cells. (PMID:18056395)
somatic mutation of the CASP4 gene is common in gastrointestinal stromal tumor & suggest a possibility that CASP4 mutation might lead to alteration of apoptotic or inflammatory function & contribute to pathogenesis of some gastrointestinal stromal tumors (PMID:19269008)
This study suggests a possible role of caspase-4 in the apoptotic loss of proximal tubular cells. (PMID:19705160)
results show that activation of caspase-4 contributes to TRAIL-induced apoptosis and is associated with induction of ER stress by TRAIL in melanoma cells (PMID:20514521)
Neuronal cell death is induced via cleavage of caspase-4 in endoplasmic reticulum cells under stress in vitro. (PMID:20816908)
results suggest that caspase-4 directly activates caspase-9 by the processing of procaspase-9 at Asp-315 in endoplasmic reticulum stress-induced neuronal apoptosis (PMID:21282934)
Data suggest that Casp4, Casp 6 and TNFSF10 are differentially expressed in potentially fertile and subfertile men and represent useful biomarkers for predicting male fertility in combination with P1 and P2. (PMID:21317160)
GRP78, CHOP, caspase 4, and caspase 3 may be involved in adenosine-induced HepG2 cell apoptosis (PMID:21479362)
Loss of heterozygosity contributes to tumor progression of oral squamous cell carcinoma, and a specific role for PDCD4, CTNNB1, and CASP4 was found. (PMID:21781452)
Levels of c-Rel directly modulated expression of caspase-4 as well as other endoplasmic reticulum stress genes. (PMID:21984918)
Caspase-4 expression is essential for efficient nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 and for absent in melanoma 2 inflammasome-dependent proIL-1beta activation in macrophages (PMID:22246630)
These experiments identify caspase 4 as a novel regulator of TNF-alpha-induced NF-kappaB signaling that is required for the activation of I-kappaB kinase. (PMID:22733992)
TMEM214 is essential for endoplasmic reticulum (ER) stress-induced apoptosis by acting as an anchor for recruitment of procaspase 4 to the ER and its subsequent activation. (PMID:23661706)
Shigella OspC3 interacts with the caspase-4-p19 subunit and inhibits its activation by preventing caspase-4-p19 and caspase-4-p10 heterodimerization. (PMID:23684308)
TLR3 stimulation in keratinocytes induces a caspase-4 dependent release of pro-IL-1beta, but further processing to active IL-1beta is limited. Furthermore, TLR3 stimulation results in pyroptotic- and apoptotic cell death. (PMID:23845419)
Authors observed increases in the endoplasmic reticulum stress markers BiP and cleaved caspase-4 in Duchenne muscular dystrophy patient biopsies, compared with controls. (PMID:24879640)
caspase-4 can support activation of caspase-1 and secretion of IL-1beta and IL-18 in response to priming signals (LPS or Pam3CSK4) alon (PMID:24879791)
function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation (PMID:25119034)
The caspase-4/11 inflammasome also governs activation of the proinflammatory cytokine, interleukin (IL)-18, in response to intracellular and extracellular enteric pathogens. (PMID:25121752)
This study reveled that CASP4 having a central role in the bipolar disease and schizophrenia manifestation. (PMID:25487697)
NF-kappaB can mediate Fas-induced apoptosis through caspase-4 protease (PMID:25695505)
this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in colorectal cancer. (PMID:25943872)
implicate caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary macrophages (PMID:25964352)
both caspase-4 and caspase-5 are functionally important for appropriate responses to intracellular Gram-negative bacteria. (PMID:26173988)
caspase-4 activation alone is sufficient to induce pyroptosis, this process depends on the NLRP3 inflammasome activation to drive IL-1beta maturation. (PMID:26174085)
Caspase-4 and caspase-5 mediate IL-1alpha and IL-1beta release from human monocytes after lipopolysaccharides stimulation. (PMID:26508369)
apoptosis is induced by rhein traditional Chinese medicine via induction of endoplasmic reticulum stress, caspase-4 and intracellular calcium in primary human hepatic HL-7702 cells (PMID:27003256)
Pathophysiological studies showed that the overexpression of the CASP4 gene was involved in the loss of proximal tubules and renal injury in nephropathic cystinosis patients. Considering kidney’s key roles in sodium filtration and reabsorption CASP4 genes are involved in Blood Pressure regulation. (PMID:27271309)
Specific activation of caspase-3 and caspase-4 was found in proplatelets. Consistent with previous observations of caspase-4 autoactivation in response to endoplasmic reticulum (ER) stress, several ER stress marker proteins were expressed during proplatelet formation. (PMID:27296088)
We propose that microglial caspase-4 expression contributes to the cognitive impairments in Alzheimer’s disease (AD), and that further study of caspase-4 will enhance our understanding of AD pathogenesis and may lead to novel therapeutic targets in AD. (PMID:27516385)
this study shows that activation of caspase-4 is mediated by interactions with endotoxin-rich membrane interfaces rather than by endotoxin monomers (PMID:28409545)
The last four amino acids of the NleF carboxy terminus are essential in inhibiting caspase-4-dependent inflammatory cell death. (PMID:28593173)
The results demonstrate that cathepsin G is directly engaged in caspase-4 activation by a bacterial ligand, which is responsible for cell death and IL-1alpha secretion in HGFs. (PMID:29077095)
Results implicate pyroptosis induced by the CASP11/4-GSDMD pathway in the pathogenesis of alcoholic hepatitis (PMID:29108122)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp8	ENSDARG00000058325
danio_rerio	casp3l	ENSDARG00000086266
danio_rerio	casp20	ENSDARG00000104367
danio_rerio		ENSDARG00000112575
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000819
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP6 (ENSG00000138794), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Protein

Protein identifiers

Caspase-4 — P49662 (reviewed: P49662)

Alternative names: ICE and Ced-3 homolog 2, ICE(rel)-II, Mih1, Protease TX

All UniProt accessions (3): E9PMT1, P49662, H0YD34

UniProt curated annotations — full annotation on UniProt →

Function. Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis. Also indirectly activates the NLRP3 and NLRP6 inflammasomes. Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18. Effector of the non-canonical inflammasome independently of NLRP3 inflammasome and CASP1: the non-canonical inflammasome promotes pyroptosis through GSDMD cleavage without involving secretion of cytokine IL1B. In the non-canonical inflammasome, CASP4 is activated by direct binding to the lipid A moiety of LPS without the need of an upstream sensor. LPS-binding promotes CASP4 activation and CASP4-mediated cleavage of GSDMD and IL18, followed by IL18 secretion through the GSDMD pore, pyroptosis of infected cells and their extrusion into the gut lumen. Also indirectly promotes secretion of mature cytokines (IL1A and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes. Involved in NLRP3-dependent CASP1 activation and IL1B secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin. Involved in NLRP6 inflammasome-dependent activation in response to lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, which leads to CASP1 activation and IL1B secretion. Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity. The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria. Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection. Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation. May also act as an activator of adaptive immunity in dendritic cells, following activation by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer’s patient brains. Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part. Catalyzes cleavage and maturation of IL18; IL18 processing also depends of the exosite interface on CASP4. In contrast, it does not directly process IL1B. During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation. (Microbial infection) In response to the Td92 surface protein of the periodontal pathogen T.denticola, activated by cathepsin CTSG which leads to production and secretion of IL1A and pyroptosis of gingival fibroblasts.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit. Upon direct LPS-binding, forms large homooligomers, resulting in its activation. These oligomers are often referred to as ’non-canonical inflammasomes’. In its precursor form, interacts with TMEM214; this interaction is required for association with the endoplasmic reticulum membrane. Interacts with CASP1. Interacts with NOD2. Interacts with SERPINB1; this interaction regulates CASP4 activity. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit. (Microbial infection) Interacts with NleF protein from pathogenic E.coli; this interaction leads to enzyme inhibition. (Microbial infection) Interacts with cathepsin CTSG; the interaction is promoted by the Td92 surface protein of the periodontal pathogen T.denticola and leads to CASP4 activation.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum membrane. Mitochondrion. Inflammasome. Secreted.

Tissue specificity. Widely expressed, including in keratinocytes and colonic and small intestinal epithelial cells (at protein level). Not detected in brain.

Post-translational modifications. In response to activation signals, undergoes autoproteolytic cleavage and activation. (Microbial infection) ADP-riboxanation by S.flexneri OspC3 blocks CASP4 autoprocessing, preventing CASP4 activation and ability to recognize and cleave GSDMD, thereby thwarting the inflammasome/pyroptosis-mediated defense.

Activity regulation. Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner. In addition to LPS, CASP4/CASP11 may also be activated by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC), in dendritic cells, promoting adaptive immunity. The role of oxPAPC is however unclear and another report suggests that oxPAPC competes with LPS-binding and inhibits the non-canonical inflammasome in macrophages.

Domain organisation. The CARD domain mediates LPS recognition and homooligomerization.

Induction. In peripheral blood mononuclear cells and purified monocytes, up-regulated by bacterial lipopolysaccharides (LPS) and interferon-beta/IFNB1 at the mRNA level. However, this increase is not observed at the protein level, which remains constant in monocytes and other cell types following LPS treatment. In monocyte-derived macrophages, some up-regulation at the protein level is observed following treatment with LPS and IFNB1. In SH-EP1 neuroblastoma cell line, up-regulated by NF-kappa-B RELA/p65 at both mRNA and protein levels.

Miscellaneous. May be due to competing acceptor splice site. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the peptidase C14A family.

Isoforms (5)

UniProt ID	Names	Canonical?
P49662-1	1, Alpha	yes
P49662-2	2, Gamma, mih1-beta
P49662-3	3, mih1-delta
P49662-4	4
P49662-5	5

RefSeq proteins (2): NP_001216, NP_150649 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001309	Pept_C14_p20	Domain
IPR001315	CARD	Domain
IPR002138	Pept_C14_p10	Domain
IPR002398	Pept_C14	Family
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR011600	Pept_C14_caspase	Domain
IPR015917	Pept_C14A	Domain
IPR016129	Caspase_his_AS	Active_site
IPR029030	Caspase-like_dom_sf	Homologous_superfamily
IPR033139	Caspase_cys_AS	Active_site

Pfam: PF00619, PF00656

Enzyme classification (BRENDA):

EC 3.4.22.57 — caspase-4 (BRENDA: 6 organisms, 73 substrates, 24 inhibitors, 30 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ACETYL-WEHD-7-AMIDO-4-METHYLCOUMARIN	0.017–0.079	4
ACETYL-FEAD-7-AMIDO-4-METHYLCOUMARIN	0.019–0.021	2
ACETYL-WQPD-7-AMIDO-4-METHYLCOUMARIN	0.016–0.073	2
SUCCINYL-YVAD-4-NITROANILIDE	0.048–0.09	2
ACETYL-DEVD-4-NITROANILIDE	0.032	1
ACETYL-DQMD-4-NITROANILIDE	0.35	1
ACETYL-LEVD-4-NITROANILIDE	0.044	1
ACETYL-LEVDGW-AMIDE	0.43	1
ACETYL-TYR-VAL-ALA-ASP-4-NITROANILIDE	0.681	1
ACETYL-VEID-4-NITROANILIDE	0.205	1
ACETYL-VQVD-4-NITROANILIDE	0.72	1
ACETYL-YEVD-4-NITROANILIDE	0.031	1
ACETYL-YVAD-4-NITROANILIDE	0.874	1
ACETYL-YVAD-AMIDO-4-METHYLCOUMARIN	0.035	1
LLSDGID	0.022	1

UniProt features (68 total): mutagenesis site 14, helix 14, strand 13, splice variant 7, modified residue 3, sequence variant 3, turn 3, propeptide 2, chain 2, region of interest 2, active site 2, domain 1, initiator methionine 1, site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
7WR6	X-RAY DIFFRACTION	1.96
7WR1	X-RAY DIFFRACTION	2.13
6NRY	X-RAY DIFFRACTION	2.18
7WR4	X-RAY DIFFRACTION	2.75
7WR0	X-RAY DIFFRACTION	2.8
7WR5	X-RAY DIFFRACTION	3.1
8J6K	X-RAY DIFFRACTION	3.12
8SPB	ELECTRON MICROSCOPY	3.2
6KMZ	X-RAY DIFFRACTION	3.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49662-F1	79.00	0.52

Functional residue map

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

Catalytic / active sites (3): 210; 258; 289–290 (cleavage; by autolysis)

Post-translational modifications (3): 83, 314, 2

Mutagenesis-validated functional residues (14):

Position	Phenotype
152	abolished ability to cleave il18.
212	abolished ability to cleave il18; when associated with d-261.
258	loss of enzymatic activity. loss of lps-induced pyroptosis. no effect on the interaction with lps. decrease in cell deat
258	loss of autocatalysis.
261	abolished ability to cleave il18; when associated with d-212.
267	abolished interaction with gasdermin-d (gsdmd) and ability to mediate its cleavage. abolished binding to il18 and abilit
269	abolished binding to il18 and ability to mediate its cleavage.
270	abolished autoprocessing and ability to form a heterotetramer composed of caspase-4 subunit p10 and caspase-4 subunit p2
289	abolished autoprocessing.
291	abolished interaction with gasdermin-d (gsdmd) and ability to mediate its cleavage. strongly decreased ability to cleave
293	strongly decreased ability to cleave il18.
314	abolished ability to cleave gasdermin-d (gsdmd). abolished ability to cleave il18.
321	abolished ability to cleave il18.
356	abolished binding to il18 and ability to mediate its cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-5620971	Pyroptosis
R-HSA-9948001	CASP4 inflammasome assembly
R-HSA-9956593	Enterobacterial factors antagonize host defense
R-HSA-9960519	CASP4-mediated substrate cleavage
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-5218859	Regulated Necrosis
R-HSA-5357801	Programmed Cell Death

MSigDB gene sets: 434 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, MODULE_172, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_INFLAMMATORY_RESPONSE, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, chr11q22, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MODULE_45, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (25): proteolysis (GO:0006508), apoptotic process (GO:0006915), protein autoprocessing (GO:0016540), defense response to bacterium (GO:0042742), positive regulation of neuron apoptotic process (GO:0043525), innate immune response (GO:0045087), regulation of inflammatory response (GO:0050727), positive regulation of inflammatory response (GO:0050729), defense response to Gram-positive bacterium (GO:0050830), protein maturation (GO:0051604), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), pyroptotic inflammatory response (GO:0070269), intrinsic apoptotic signaling pathway (GO:0097193), non-canonical inflammasome complex assembly (GO:0160075), positive regulation of tumor necrosis factor-mediated signaling pathway (GO:1903265), cellular response to amyloid-beta (GO:1904646), positive regulation of interleukin-18-mediated signaling pathway (GO:2000494), immune system process (GO:0002376), inflammatory response (GO:0006954), protein secretion (GO:0009306), programmed cell death (GO:0012501), interleukin-18-mediated signaling pathway (GO:0035655), regulation of apoptotic process (GO:0042981), NLRP3 inflammasome complex assembly (GO:0044546), pyroptotic cell death (GO:0141201)

GO Molecular Function (8): lipopolysaccharide binding (GO:0001530), cysteine-type endopeptidase activity (GO:0004197), lipid binding (GO:0008289), CARD domain binding (GO:0050700), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (12): extracellular region (GO:0005576), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), protein-containing complex (GO:0032991), NLRP1 inflammasome complex (GO:0072558), non-canonical inflammasome complex (GO:0160074), membrane (GO:0016020), canonical inflammasome complex (GO:0061702)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Non-canonical inflammasome activation	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Regulated Necrosis	1
Infection with Enterobacteria	1
Immune System	1
Innate Immune System	1
Programmed Cell Death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
inflammatory response	3
cytoplasm	3
protein metabolic process	2
apoptotic signaling pathway	2
defense response	2
positive regulation of cytokine-mediated signaling pathway	2
binding	2
intracellular membrane-bounded organelle	2
cytosol	2
protein-containing complex	2
programmed cell death	1
execution phase of apoptosis	1
protein processing	1
response to bacterium	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
immune response	1
defense response to symbiont	1
regulation of defense response	1
regulation of response to external stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
defense response to bacterium	1
gene expression	1
response to endoplasmic reticulum stress	1
intrinsic apoptotic signaling pathway	1
intracellular signal transduction	1
protein-containing complex assembly	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to amyloid-beta	1
interleukin-18-mediated signaling pathway	1
regulation of interleukin-18-mediated signaling pathway	1
biological_process	1
protein transport	1

Protein interactions and networks

STRING

1566 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP4	CASP1	P29466	921
CASP4	NLRC4	Q9NPP4	863
CASP4	SCAF11	Q99590	860
CASP4	IL1B	P01584	830
CASP4	NLRP1	Q9C000	750
CASP4	GSDMD	P57764	739
CASP4	NLRP6	P59044	720
CASP4	AIM2	O14862	718
CASP4	IL6	P05231	674
CASP4	IFNG	P01579	632
CASP4	GSDME	O60443	631
CASP4	HSPA5	P11021	624
CASP4	IRF1	P10914	619
CASP4	DDIT3	P35638	618
CASP4	PYCARD	Q9ULZ3	614

IntAct

48 interactions, top by confidence:

A	B	Type	Score
CASP5	CASP4	psi-mi:“MI:0914”(association)	0.530
CASP4	ARHGAP44	psi-mi:“MI:0915”(physical association)	0.500
GSDMD	CASP4	psi-mi:“MI:0570”(protein cleavage)	0.440
NOD2	CASP4	psi-mi:“MI:0915”(physical association)	0.400
CASP4	nleF	psi-mi:“MI:0915”(physical association)	0.400
ELF4	CASP4	psi-mi:“MI:0915”(physical association)	0.370
MYH9	CASP4	psi-mi:“MI:0915”(physical association)	0.370
CASP4	NME2P1	psi-mi:“MI:0914”(association)	0.350
SGIP1	SPAG6	psi-mi:“MI:0914”(association)	0.350
CASP4	SMC3	psi-mi:“MI:0915”(physical association)	0.000
CASP4	SNRPA1	psi-mi:“MI:0915”(physical association)	0.000
CASP4	SSR4	psi-mi:“MI:0915”(physical association)	0.000
CASP4	PSMB1	psi-mi:“MI:0915”(physical association)	0.000
CASP4	SMC2	psi-mi:“MI:0915”(physical association)	0.000
CASP4	SMC1A	psi-mi:“MI:0915”(physical association)	0.000
CASP4	LSM10	psi-mi:“MI:0915”(physical association)	0.000
CASP4	DCTN1	psi-mi:“MI:0915”(physical association)	0.000
CASP4	CTNNBIP1	psi-mi:“MI:0915”(physical association)	0.000
CASP4	EIF2S3	psi-mi:“MI:0915”(physical association)	0.000
CASP4	UBXN1	psi-mi:“MI:0915”(physical association)	0.000
CASP4	MDN1	psi-mi:“MI:0915”(physical association)	0.000
CASP4	GCN1	psi-mi:“MI:0915”(physical association)	0.000
CASP4	COPE	psi-mi:“MI:0915”(physical association)	0.000
CASP4	DNAAF5	psi-mi:“MI:0915”(physical association)	0.000
CASP4		psi-mi:“MI:0915”(physical association)	0.000
CASP4	NUP93	psi-mi:“MI:0915”(physical association)	0.000
CASP4	USP9X	psi-mi:“MI:0915”(physical association)	0.000
CASP4	SMC4	psi-mi:“MI:0915”(physical association)	0.000
CASP4	SNRNP200	psi-mi:“MI:0915”(physical association)	0.000
CASP4	VDAC1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (50): CASP4 (Reconstituted Complex), CASP4 (Affinity Capture-Western), CASP4 (Affinity Capture-MS), SMC3 (Affinity Capture-MS), MTHFD1L (Affinity Capture-MS), GSN (Affinity Capture-MS), DNAAF5 (Affinity Capture-MS), SRPRB (Affinity Capture-MS), NUP93 (Affinity Capture-MS), MYCBPAP (Affinity Capture-MS), SLC25A22 (Affinity Capture-MS), SMC1A (Affinity Capture-MS), CDK2 (Affinity Capture-MS), PSMB1 (Affinity Capture-MS), SMC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L1SUL6, F1NV61, O08736, O08738, O15519, O35397, O75601, O89110, O95453, P29452, P29466, P43527, P49662, P51878, P54281, P55212, P69341, P70343, P70677, P97864, Q075B4, Q08DY9, Q14790, Q153Z0, Q2PFV2, Q2TBA3, Q3T0P5, Q3U2J5, Q4AC99, Q5E9C1, Q5RC51, Q5RD56, Q6GQ33, Q6UXS9, Q7SY78, Q8BYN3, Q8K4Q7, Q8MJC3, Q8MJU1, Q8MKI5

Diamond homologs: O08736, O35397, O75601, P29452, P29466, P42574, P43527, P49662, P51878, P55212, P55213, P55865, P55867, P70343, P70677, Q075B4, Q08DY9, Q153Z0, Q2PFV2, Q504J1, Q5E9C1, Q5IS54, Q5IS99, Q60431, Q6UXS9, Q8MJC3, Q8MJU1, Q8MKI5, Q920D5, Q95ND5, Q9I9L7, Q9MZV6, Q9MZV7, Q9N2I1, Q9TV13, F1NV61, Q5EG05, O08738, O89094, P29594

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CASP4	“up-regulates activity”	GSDMD	cleavage
TSHZ3	“down-regulates quantity by repression”	CASP4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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.

GO biological processes:

GO term	Partners	Fold	FDR
cell division	7	7.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1443 predictions. Top by Δscore:

Variant	Effect	Δscore
11:104944745:A:AC	donor_gain	1.0000
11:104944745:AAC:A	donor_gain	1.0000
11:104944746:A:C	donor_gain	1.0000
11:104949536:CACTC:C	donor_loss	1.0000
11:104949537:ACTC:A	donor_loss	1.0000
11:104949538:CT:C	donor_loss	1.0000
11:104949540:CACCA:C	donor_loss	1.0000
11:104949542:CCA:C	donor_gain	1.0000
11:104949774:TATC:T	acceptor_gain	1.0000
11:104949774:TATCC:T	acceptor_loss	1.0000
11:104949776:TC:T	acceptor_gain	1.0000
11:104949776:TCC:T	acceptor_loss	1.0000
11:104949777:CC:C	acceptor_gain	1.0000
11:104949777:CCTG:C	acceptor_loss	1.0000
11:104949778:C:CC	acceptor_gain	1.0000
11:104949778:CT:C	acceptor_loss	1.0000
11:104949779:T:A	acceptor_loss	1.0000
11:104950923:AC:A	donor_gain	1.0000
11:104950924:CC:C	donor_gain	1.0000
11:104942970:CTTC:C	acceptor_gain	0.9900
11:104942971:TTCC:T	acceptor_loss	0.9900
11:104942972:TCC:T	acceptor_loss	0.9900
11:104942974:C:CC	acceptor_gain	0.9900
11:104942975:T:C	acceptor_loss	0.9900
11:104944589:A:C	acceptor_gain	0.9900
11:104944620:CCAGA:C	acceptor_gain	0.9900
11:104944621:CAGAC:C	acceptor_gain	0.9900
11:104944625:C:CC	acceptor_gain	0.9900
11:104944780:T:C	donor_gain	0.9900
11:104947193:C:CC	acceptor_gain	0.9900

AlphaMissense

2510 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:104951033:A:C	F146L	0.996
11:104951033:A:T	F146L	0.996
11:104951035:A:G	F146L	0.996
11:104949718:G:C	S202R	0.991
11:104949718:G:T	S202R	0.991
11:104949720:T:G	S202R	0.991
11:104944837:A:C	F350L	0.984
11:104944837:A:T	F350L	0.984
11:104944839:A:G	F350L	0.984
11:104949547:T:A	R259S	0.984
11:104949547:T:G	R259S	0.984
11:104944808:G:T	P360H	0.983
11:104949571:C:A	K251N	0.982
11:104949571:C:G	K251N	0.982
11:104949751:A:C	F191L	0.980
11:104949751:A:T	F191L	0.980
11:104949753:A:G	F191L	0.980
11:104949548:C:G	R259T	0.979
11:104949619:G:C	F235L	0.978
11:104949619:G:T	F235L	0.978
11:104949621:A:G	F235L	0.978
11:104951015:C:A	R152S	0.978
11:104951015:C:G	R152S	0.978
11:104947087:C:G	R344P	0.977
11:104949577:T:A	K249N	0.975
11:104949577:T:G	K249N	0.975
11:104949692:C:A	G211V	0.973
11:104949555:C:G	A257P	0.971
11:104949692:C:T	G211D	0.971
11:104949699:A:G	S209P	0.971

dbSNP variants (sampled 300 via entrez): RS1000087858 (11:104962954 G>A,T), RS1000268679 (11:104946392 G>A,C), RS1000458409 (11:104963157 T>C), RS1000554274 (11:104960328 A>G,T), RS1000601173 (11:104945182 C>G), RS1000664457 (11:104969641 A>C), RS1000882505 (11:104957843 G>A,C), RS1000913422 (11:104954450 C>T), RS1000915062 (11:104957607 T>A,C), RS1001225479 (11:104969417 T>C), RS1001261894 (11:104948025 T>C), RS1001555011 (11:104960525 A>G,T), RS1001581396 (11:104957157 C>A), RS1001586147 (11:104960248 G>A,C,T), RS1001699757 (11:104944641 A>G)

Disease associations

OMIM: gene MIM:602664 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005231_57	Major depressive disorder	7.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2226 (SINGLE PROTEIN), CHEMBL3831289 (PROTEIN FAMILY)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C14: Caspase

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
VRT-043198	Inhibition	9.4	pKi
M826	Inhibition	6.52	pIC50
casp 4 inhib	Inhibition	5.4	pKi

Binding affinities (BindingDB)

14 measured of 28 human assays (28 total across all organisms); most potent 14 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-{[(4-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}phenyl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	160 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]pyridin-2-ylmethyl}sulfamoyl)-2-hydroxy-benzoic Acid	KI	1500 nM
Thiophene Scaffold 66a	KI	1900 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-phenylacetyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	2000 nM	US-9045524: Selective caspase inhibitors and uses thereof
Heterocyclic deriv. 69b	KI	2700 nM
Thiophene Scaffold 66b	KI	3200 nM
Pyridine Scaffold 4	KI	3900 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]thiazol-2-hydroxy-benzoic Acidylmethyl}sulfamoyl)-2-	KI	8300 nM
5-(pyrrolidine-1-sulfonyl)-2,3-dihydro-1H-indole-2,3-dione	KI	9000 nM
1-methyl-5-nitro-2,3-dihydro-1H-indole-2,3-dione	KI	12000 nM
5-({(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}thiophen-2-yl)methylamino}methyl)-2-hydroxybenzoic acid	KI	12000 nM
1-benzyl-5-nitro-2,3-dihydro-1H-indole-2,3-dione	KI	18000 nM
5-{[(2S)-2-[(phenylamino)methyl]pyrrolidine-1-]sulfonyl}-2,3-dihydro-1H-indole-2,3-dione	KI	21000 nM
5-{[(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}pyrimidin-2-yl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	25000 nM

ChEMBL bioactivities

41 potent at pChembl≥5 of 52 total, top 41 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.10	Ki	8	nM	CHEMBL3949842
7.80	EC50	16	nM	CHEMBL1091826
7.68	IC50	21	nM	CHEMBL3949842
7.09	IC50	81.7	nM	CHEMBL5715921
7.08	IC50	84	nM	CHEMBL5715925
7.05	IC50	90	nM	CHEMBL2323966
6.92	Ki	119	nM	CHEMBL3970645
6.83	Ki	148	nM	CHEMBL3941088
6.75	IC50	180	nM	CHEMBL2324340
6.68	Ki	207	nM	CHEMBL3905486
6.67	Ki	215	nM	CHEMBL3984293
6.61	Ki	248	nM	CHEMBL3898379
6.57	Ki	267	nM	CHEMBL3904435
6.56	Ki	276	nM	CHEMBL3939229
6.52	IC50	300	nM	CHEMBL366927
6.51	Ki	306	nM	CHEMBL3978901
6.50	IC50	320	nM	CHEMBL3970645
6.47	Ki	337	nM	CHEMBL1412861
6.43	IC50	370	nM	CHEMBL2324339
6.41	Ki	393	nM	CHEMBL3965572
6.40	IC50	400	nM	CHEMBL3941088
6.30	IC50	500	nM	CHEMBL179503
6.29	IC50	510	nM	CHEMBL2324341
6.25	IC50	560	nM	CHEMBL3905486
6.25	Ki	563	nM	CHEMBL3968765
6.24	IC50	580	nM	CHEMBL3984293
6.17	IC50	670	nM	CHEMBL3898379
6.14	IC50	721	nM	CHEMBL3904435
6.13	IC50	746	nM	CHEMBL3939229
6.08	IC50	826	nM	CHEMBL3978901
6.06	Ki	870	nM	CHEMBL3895496
6.04	IC50	909	nM	CHEMBL1412861
5.97	IC50	1060	nM	CHEMBL3965572
5.82	IC50	1520	nM	CHEMBL3968765
5.63	IC50	2350	nM	CHEMBL3895496
5.55	IC50	2800	nM	CHEMBL3673262
5.40	Ki	4000	nM	CHEMBL293622
5.30	IC50	5000	nM	GRASSYSTATIN A
5.30	Ki	5000	nM	CHEMBL60306
5.25	IC50	5600	nM	CHEMBL2323967
5.09	IC50	8128	nM	CHEMBL568171

PubChem BioAssay actives

46 with measured affinity, of 106 total; 31 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-[4-(2-phenylethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0080	uM
N-(4-methoxyphenyl)-N-methyl-1,2,3-benzotriazin-4-amine	1393168: Activation of caspase cascade in human T47D cells using N-(Ac-DEVD)-N’-ethoxycarbonyl-R110 fluorogenic substrate incubated for 48 hrs by fluorescent plate reader based assay	ec50	0.0160	uM
(E,3S)-3-[[(2S)-1-[(2R)-2-[(4-amino-3-chlorobenzoyl)amino]-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-5-methylsulfonylpent-4-enoic acid	726066: Inhibition of caspase-4 (unknown origin)	ic50	0.0900	uM
[4-[[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]methyl]phenyl]-phenylmethanone	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.1190	uM
4-[4-[(3,5-dimethoxyphenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.1480	uM
(E,3S)-3-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-3-(1H-indol-3-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-5-methylsulfonylpent-4-enoic acid	726066: Inhibition of caspase-4 (unknown origin)	ic50	0.1800	uM
4-piperazin-1-yl-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.2070	uM
4-[4-[(4-nitrophenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.2150	uM
3-[[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]methyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-6-ol	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.2480	uM
4-[4-[(2-nitrophenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.2670	uM
4-[4-[(3-methoxyphenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.2760	uM
3-[2-[5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-[hexyl(methyl)amino]-4-oxopentanoic acid;hydrochloride	241193: Inhibitory concentration against human caspase-4 in neuronal precursor (NT2) cells	ic50	0.3000	uM
4-[4-(cyclohexylmethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.3060	uM
(8S,10S,13S,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.3370	uM
(E,3S)-3-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-5-methylsulfonylpent-4-enoic acid	726066: Inhibition of caspase-4 (unknown origin)	ic50	0.3700	uM
2-(5-benzoylthiophen-2-yl)propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.3800	uM
4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.3930	uM
3-[2-[5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-[methyl(pentyl)amino]-4-oxopentanoic acid;hydrochloride	241867: Inhibitory concentration against casp-4 in neuronal precursor (NT2) cells	ic50	0.5000	uM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-phenylacetyl]amino]-3-methylbutanoyl]amino]-6-ethoxy-6-oxohex-4-enoic acid	726066: Inhibition of caspase-4 (unknown origin)	ic50	0.5100	uM
2,4-dipyrrolidin-1-yl-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]pyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.5630	uM
4-oxo-4-(4-phenylphenyl)butanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.5700	uM
2-[4-(3-oxo-1H-isoindol-2-yl)phenyl]propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.5700	uM
Ketorolac	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.8600	uM
4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325503: Inhibition of human recombinant N-terminal His-tagged DTT-activated caspase-4 expressed in Escherichia coli using Ac-LEVD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.8700	uM
2-(4-phenylphenyl)acetic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	2.0000	uM
1-methyl-5-nitroindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	4.0000	uM
1-benzyl-5-nitroindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	5.0000	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S,3R)-2-[[(3S,4S)-4-[[(2S)-4-amino-2-[[(2S)-2-[[(2R)-2-[(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanoyl]oxy-3-methylbutanoyl]oxy-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxy-6-methylheptanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	448862: Inhibition of caspase 4 after 10 to 15 mins by fluorescence assay	ic50	5.0000	uM
(E,3S)-3-[[(2S)-1-[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3,3-dimethylbutanoyl]azetidine-2-carbonyl]amino]-5-methylsulfonylpent-4-enoic acid	726066: Inhibition of caspase-4 (unknown origin)	ic50	5.6000	uM
4-(cyclopentylamino)-6-(3,5-difluoroanilino)-1,3,5-triazine-2-carbonitrile	444694: Inhibition of human Caspase 4	ic50	8.1283	uM
2-[4-(2-methylpropyl)phenyl]propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	8.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	affects cotreatment, decreases reaction, increases cleavage, affects binding, increases activity (+1 more)	6
Resveratrol	increases cleavage, affects response to substance, affects cotreatment, decreases reaction, increases expression (+2 more)	4
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	4
bisphenol A	decreases expression, decreases methylation, increases expression	3
Acetaminophen	decreases expression	3
Capsaicin	increases activity, increases cleavage	3
Paclitaxel	affects cotreatment, increases expression, decreases cleavage	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
usnic acid	increases cleavage, increases expression	2
(+)-JQ1 compound	decreases expression	2
Bortezomib	increases reaction, decreases reaction, affects cotreatment, increases activity, increases cleavage (+1 more)	2
Vorinostat	affects cotreatment, increases activity, increases reaction	2
Acetylcysteine	increases activity, affects cotreatment, increases cleavage, decreases reaction	2
Air Pollutants	decreases expression, increases expression	2
Arsenic	decreases expression, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Cisplatin	increases response to substance, affects cotreatment, increases activity	2
Fluorouracil	affects response to substance, increases expression	2
Quercetin	increases expression	2
Silver	increases expression	2
Cyclosporine	increases expression	2
Thapsigargin	increases activity, increases reaction, increases cleavage	2
Magnetite Nanoparticles	affects cotreatment, increases expression, decreases expression	2
tetrachlorobenzoquinone	increases cleavage	1
bisphenol F	decreases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
sanguinarine	affects cotreatment, increases expression	1
propylparaben	increases expression	1

ChEMBL screening assays

22 unique, capped per target: 21 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1039233	Binding	Inhibition of caspase 4 after 10 to 15 mins by fluorescence assay	Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. — J Med Chem
CHEMBL5723118	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002201a CASP4	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AP	THP1-KO-CASP4	Cancer cell line	Male
CVCL_C7D5	Abcam A-549 CASP4 KO	Cancer cell line	Male
CVCL_C7DV	Abcam HCT 116 CASP4 KO	Cancer cell line	Male
CVCL_C7EJ	Abcam THP-1 CASP4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.