Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH39BKI)

• DOT Name: Gasdermin-D (GSDMD)
• Synonyms: Gasdermin domain-containing protein 1
• Gene Name: GSDMD
• Related Disease:
  Acute liver failure
  Acute myocardial infarction
  Adult respiratory distress syndrome
  Advanced cancer
  Alcoholic hepatitis
  Chronic kidney disease
  CINCA syndrome
  Cytomegalovirus infection
  Diabetic kidney disease
  Disorder of sexual differentiation
  Familial Mediterranean fever
  Fatty liver disease
  Gram-negative bacterial infection
  Inflammatory bowel disease
  Knee osteoarthritis
  Melioidosis
  Multiple sclerosis
  Neoplasm
  Nervous system inflammation
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Non-small-cell lung cancer
  Bacterial infection
  Gastric cancer
  Schwannoma
  Asthma
  Ocular hypertension
  Periodic fever syndrome
  Stomach cancer
• UniProt ID: GSDMD_HUMAN
• PDB ID: 5NH1; 5WQT; 6AO4; 6KN0; 6N9O; 6VFE; 7Z1X
• Pfam ID: PF04598 ; PF17708
• Sequence:
  MGSAFERVVRRVVQELDHGGEFIPVTSLQSSTGFQPYCLVVRKPSSSWFWKPRYKCVNLS
  IKDILEPDAAEPDVQRGRSFHFYDAMDGQIQGSVELAAPGQAKIAGGAAVSDSSSTSMNV
  YSLSVDPNTWQTLLHERHLRQPEHKVLQQLRSRGDNVYVVTEVLQTQKEVEVTRTHKREG
  SGRFSLPGATCLQGEGQGHLSQKKTVTIPSGSTLAFRVAQLVIDSDLDVLLFPDKKQRTF
  QPPATGHKRSTSEGAWPQLPSGLSMMRCLHNFLTDGVPAEGAFTEDFQGLRAEVETISKE
  LELLDRELCQLLLEGLEGVLRDQLALRALEEALEQGQSLGPVEPLDGPAGAVLECLVLSS
  GMLVPELAIPVVYLLGALTMLSETQHKLLAEALESQTLLGPLELVGSLLEQSAPWQERST
  MSLPPGLLGNSWGEGAPAWVLLDECGLELGEDTPHVCWEPQAQGRMCALYASLALLSGLS
  QEPH
• Function: [Gasdermin-D]: Precursor of a pore-forming protein that plays a key role in host defense against pathogen infection and danger signals. This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-D, N-terminal) binds to membranes and forms pores, triggering pyroptosis ; [Gasdermin-D, N-terminal]: Promotes pyroptosis in response to microbial infection and danger signals. Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1, CASP4 or CASP5 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators. After cleavage, moves to the plasma membrane where it strongly binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)-bisphosphate, and more weakly to phosphatidic acid and phosphatidylserine. Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukin-1 (IL1B and IL18) and triggering pyroptosis. Gasdermin pores also allow the release of mature caspase-7 (CASP7). In some, but not all, cells types, pyroptosis is followed by pyroptotic cell death, which is caused by downstream activation of ninjurins (NINJ1 or NINJ2), which mediate membrane rupture (cytolysis). Also forms pores in the mitochondrial membrane, resulting in release of mitochondrial DNA (mtDNA) into the cytosol. Gasdermin-D, N-terminal released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity. Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes. Also active in response to MAP3K7/TAK1 inactivation by Yersinia toxin YopJ, which triggers cleavage by CASP8 and subsequent activation. Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine ; [Gasdermin-D, p13]: Transcription coactivator produced by the cleavage by CASP3 or CASP7 in the upper small intestine in response to dietary antigens. Required to maintain food tolerance in small intestine: translocates to the nucleus and acts as a coactivator for STAT1 to induce the transcription of CIITA and MHC class II molecules, which in turn induce type 1 regulatory T (Tr1) cells in upper small intestine; [Gasdermin-D, p40]: Produced by the cleavage by papain allergen. After cleavage, moves to the plasma membrane and homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the specific release of mature interleukin-33 (IL33), promoting type 2 inflammatory immune response.
• Tissue Specificity: Expressed in the suprabasal cells of esophagus, as well as in the isthmus/neck, pit, and gland of the stomach, suggesting preferential expression in differentiating cells.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  NOD-like receptor sig.ling pathway (hsa04621)
  Cytosolic D.-sensing pathway (hsa04623)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Interleukin-1 processing (R-HSA-448706)
  Pyroptosis (R-HSA-5620971)
  Regulation of TLR by endogenous ligand (R-HSA-5686938)
  Neutrophil degranulation (R-HSA-6798695)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Release of apoptotic factors from the mitochondria (R-HSA-111457)
• BioCyc Pathway: MetaCyc:ENSG00000104518-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute liver failure	DIS5EZKX	Strong	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Adult respiratory distress syndrome	DISIJV47	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alcoholic hepatitis	DISA7SH0	Strong	Biomarker	[5]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[6]
CINCA syndrome	DISU6RZC	Strong	Biomarker	[7]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[8]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[9]
Disorder of sexual differentiation	DISRMAEZ	Strong	Biomarker	[10]
Familial Mediterranean fever	DISVP5WP	Strong	Biomarker	[11]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[12]
Gram-negative bacterial infection	DIS8MM3L	Strong	Biomarker	[13]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[14]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[15]
Melioidosis	DISB13HR	Strong	Biomarker	[16]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[18]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[19]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[12]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[20]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[21]
Gastric cancer	DISXGOUK	moderate	Biomarker	[22]
Schwannoma	DISTTVLA	moderate	Biomarker	[23]
Asthma	DISW9QNS	Limited	Altered Expression	[24]
Ocular hypertension	DISC2BT9	Limited	Biomarker	[25]
Periodic fever syndrome	DIS9MNYC	Limited	Biomarker	[26]
Stomach cancer	DISKIJSX	Limited	Biomarker	[22]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Gasdermin-D (GSDMD) affects the response to substance of Paclitaxel.	[39]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Gasdermin-D (GSDMD).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Gasdermin-D (GSDMD).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Gasdermin-D (GSDMD).	[37]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Gasdermin-D (GSDMD).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Gasdermin-D (GSDMD).	[29]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Gasdermin-D (GSDMD).	[30]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Gasdermin-D (GSDMD).	[31]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the expression of Gasdermin-D (GSDMD).	[32]
Romiplostim	DM3U7SZ	Approved	Romiplostim increases the expression of Gasdermin-D (GSDMD).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Gasdermin-D (GSDMD).	[36]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Gasdermin-D (GSDMD).	[38]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ropivacaine	DMSPJG2	Approved	Ropivacaine increases the cleavage of Gasdermin-D (GSDMD).	[33]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram decreases the cleavage of Gasdermin-D (GSDMD).	[34]

References

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• [2] Cell-Specific Roles of NLRP3 Inflammasome in Myocardial Infarction.J Cardiovasc Pharmacol. 2019 Sep;74(3):188-193. doi: 10.1097/FJC.0000000000000709.
• [3] Microparticulate Caspase 1 Regulates Gasdermin D and Pulmonary Vascular Endothelial Cell Injury.Am J Respir Cell Mol Biol. 2018 Jul;59(1):56-64. doi: 10.1165/rcmb.2017-0393OC.
• [4] Induction of Pyroptosis and Its Implications in Cancer Management.Front Oncol. 2019 Sep 26;9:971. doi: 10.3389/fonc.2019.00971. eCollection 2019.
• [5] Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients.Hepatology. 2018 May;67(5):1737-1753. doi: 10.1002/hep.29645. Epub 2018 Feb 27.
• [6] Activation of GSDMD contributes to acute kidney injury induced by cisplatin.Am J Physiol Renal Physiol. 2020 Jan 1;318(1):F96-F106. doi: 10.1152/ajprenal.00351.2019. Epub 2019 Nov 4.
• [7] Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice.PLoS Biol. 2018 Nov 2;16(11):e3000047. doi: 10.1371/journal.pbio.3000047. eCollection 2018 Nov.
• [8] Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida.J Immunol. 2018 Dec 15;201(12):3662-3668. doi: 10.4049/jimmunol.1800788. Epub 2018 Nov 7.
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• [10] Exosomes Mediate Hippocampal and Cortical Neuronal Injury Induced by Hepatic Ischemia-Reperfusion Injury through Activating Pyroptosis in Rats.Oxid Med Cell Longev. 2019 Nov 13;2019:3753485. doi: 10.1155/2019/3753485. eCollection 2019.
• [11] GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever.J Exp Med. 2018 Jun 4;215(6):1519-1529. doi: 10.1084/jem.20172060. Epub 2018 May 23.
• [12] Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice.J Hepatol. 2018 Apr;68(4):773-782. doi: 10.1016/j.jhep.2017.11.040. Epub 2017 Dec 20.
• [13] A genome-wide screen identifies IRF2 as a key regulator of caspase-4 in human cells.EMBO Rep. 2019 Sep;20(9):e48235. doi: 10.15252/embr.201948235. Epub 2019 Jul 29.
• [14] NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-B signaling.Cell Death Dis. 2019 Dec 2;10(12):906. doi: 10.1038/s41419-019-2157-1.
• [15] Inhibition of Synovial Macrophage Pyroptosis Alleviates Synovitis and Fibrosis in Knee Osteoarthritis.Mediators Inflamm. 2019 Sep 8;2019:2165918. doi: 10.1155/2019/2165918. eCollection 2019.
• [16] Gasdermin D Protects from Melioidosis through Pyroptosis and Direct Killing of Bacteria.J Immunol. 2019 Jun 15;202(12):3468-3473. doi: 10.4049/jimmunol.1900045. Epub 2019 Apr 29.
• [17] Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis.Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E6065-E6074. doi: 10.1073/pnas.1722041115. Epub 2018 Jun 12.
• [18] Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.Clin Epigenetics. 2019 Apr 2;11(1):57. doi: 10.1186/s13148-019-0637-x.
• [19] Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis.J Exp Med. 2019 Nov 4;216(11):2562-2581. doi: 10.1084/jem.20190377. Epub 2019 Aug 29.
• [20] Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in nonsmall cell lung cancer.Oncol Rep. 2018 Oct;40(4):1971-1984. doi: 10.3892/or.2018.6634. Epub 2018 Aug 7.
• [21] Ion Man: GSDMD Punches Pores to Knock Out cGAS.Immunity. 2018 Sep 18;49(3):379-381. doi: 10.1016/j.immuni.2018.08.026.
• [22] Downregulation of gasdermin D promotes gastric cancer proliferation by regulating cell cycle-related proteins.J Dig Dis. 2018 Feb;19(2):74-83. doi: 10.1111/1751-2980.12576.
• [23] Schwannoma gene therapy by adeno-associated virus delivery of the pore-forming protein Gasdermin-D.Cancer Gene Ther. 2019 Sep;26(9-10):259-267. doi: 10.1038/s41417-018-0077-3. Epub 2019 Jan 9.
• [24] Rhinovirus infection induces distinct transcriptome profiles in polarized human macrophages.Physiol Genomics. 2018 May 1;50(5):299-312. doi: 10.1152/physiolgenomics.00122.2017. Epub 2018 Mar 9.
• [25] Inflammasome Activation Induces Pyroptosis in the Retina Exposed to Ocular Hypertension Injury.Front Mol Neurosci. 2019 Mar 13;12:36. doi: 10.3389/fnmol.2019.00036. eCollection 2019.
• [26] IRF2 transcriptionally induces GSDMD expression for pyroptosis.Sci Signal. 2019 May 21;12(582):eaax4917. doi: 10.1126/scisignal.aax4917.
• [27] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [28] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [29] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [30] CBD Promotes Oral Ulcer Healing via Inhibiting CMPK2-Mediated Inflammasome. J Dent Res. 2022 Feb;101(2):206-215. doi: 10.1177/00220345211024528. Epub 2021 Jul 16.
• [31] Hydroquinone triggers pyroptosis and endoplasmic reticulum stress via AhR-regulated oxidative stress in human lymphocytes. Toxicol Lett. 2023 Mar 1;376:39-50. doi: 10.1016/j.toxlet.2023.01.005. Epub 2023 Jan 13.
• [32] Activation of inflammasomes by tyrosine kinase inhibitors of vascular endothelial growth factor receptor: Implications for VEGFR TKIs-induced immune related adverse events. Toxicol In Vitro. 2021 Mar;71:105063. doi: 10.1016/j.tiv.2020.105063. Epub 2020 Dec 1.
• [33] Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway. J Toxicol Sci. 2023;48(3):139-148. doi: 10.2131/jts.48.139.
• [34] Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis. Inflamm Res. 2021 May;70(5):543-552. doi: 10.1007/s00011-021-01457-y. Epub 2021 Apr 13.
• [35] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [36] Sirtuin-1 ameliorates cadmium-induced endoplasmic reticulum stress and pyroptosis through XBP-1s deacetylation in human renal tubular epithelial cells. Arch Toxicol. 2019 Apr;93(4):965-986. doi: 10.1007/s00204-019-02415-8. Epub 2019 Feb 22.
• [37] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [38] Loganin reduces diabetic kidney injury by inhibiting the activation of NLRP3 inflammasome-mediated pyroptosis. Chem Biol Interact. 2023 Sep 1;382:110640. doi: 10.1016/j.cbi.2023.110640. Epub 2023 Jul 19.
• [39] The role of Caspase-1/GSDMD-mediated pyroptosis in Taxol-induced cell death and a Taxol-resistant phenotype in nasopharyngeal carcinoma regulated by autophagy. Cell Biol Toxicol. 2020 Oct;36(5):437-457. doi: 10.1007/s10565-020-09514-8. Epub 2020 Jan 28.