{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T21:17:26Z","timestamp":1793827046255,"version":"4.6.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Acute liver injury (ALI), often caused by viruses, alcohol, drugs, etc., is one of the most common clinical liver diseases. Although pyroptosis plays an important role in ALI, there is still a lack of effective clinical drugs related to this mechanism. Here, we show that phenethyl isothiocyanate (PEITC), a natural compound present in cruciferous vegetables, can significantly alleviate concanavalin A (ConA)-induced inflammatory liver damage and carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced chemical liver damage in a dose-dependent manner. PEITC dose-dependently reversed the ALI-induced increase in plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-\u03b1, and interferon (IFN)-\u03b3 and reduced the protein levels of hepatocyte pyroptosis markers such as Nod-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, and cleaved gasdermin D (GSDMD).<jats:italic>In vitro<\/jats:italic>experiments have also verified the inhibitory effect of PEITC on hepatocyte pyroptosis. Furthermore, PEITC inhibits pyroptosis by interacting with cysteine 191 of GSDMD. In summary, our findings establish a role for PEITC in rescuing hepatocyte pyroptosis<jats:italic>via<\/jats:italic>direct inhibition of GSDMD, which may provide a new potential therapeutic strategy for ALI.<\/jats:p>","DOI":"10.3389\/fimmu.2022.825428","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T06:40:31Z","timestamp":1643611231000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Direct Inhibition of GSDMD by PEITC Reduces Hepatocyte Pyroptosis and Alleviates Acute Liver Injury in Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Jie","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaifei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronghui","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingcai","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-315123","article-title":"Alcohol Dysregulates miR-148a in Hepatocytes Through FoxO1, Facilitating Pyroptosis","volume":"68","author":"Heo","year":"2019","journal-title":"via TXNIP overexpression Gut"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29645","article-title":"Pyroptosis by Caspase11\/4-Gasdermin-D Pathway in Alcoholic Hepatitis in Mice and Patients","volume":"67","author":"Khanova","year":"2018","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/labinvest.2013.126","article-title":"Deregulation of the NLRP3 Inflammasome in Hepatic Parenchymal Cells During Liver Cancer Progression","volume":"94","author":"Wei","year":"2014","journal-title":"Lab Invest"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.11.040","article-title":"Gasdermin D Plays a Key Role as a Pyroptosis Executor of Non-Alcoholic Steatohepatitis in Humans and Mice","volume":"68","author":"Xu","year":"2018","journal-title":"J Hepatol"},{"key":"B5","article-title":"Inhibition of Hepatic Cells Pyroptosis Attenuates CLP-Induced Acute Liver Injury","volume":"8","author":"Chen","year":"2016","journal-title":"Am J Transl Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00758","article-title":"NOD-Like Receptor Protein 3 Inflammasome-Dependent IL-1beta Accelerated ConA-Induced Hepatitis","volume":"9","author":"Luan","year":"2018","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0228-2","article-title":"The Gasdermins, a Protein Family Executing Cell Death and Inflammation","volume":"20","author":"Broz","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1016\/j.cell.2020.02.002","article-title":"Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis","volume":"180","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2016.10.004","article-title":"Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death","volume":"42","author":"Shi","year":"2017","journal-title":"Trends Biochem Sci"},{"key":"B10","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.lfs.2019.02.060","article-title":"The Relevance of Pyroptosis in the Pathogenesis of Liver Diseases","volume":"223","author":"Guo","year":"2019","journal-title":"Life Sci"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1038\/s41467-019-09397-2","article-title":"Gasdermin Pores Permeabilize Mitochondria to Augment Caspase-3 Activation During Apoptosis and Inflammasome Activation","volume":"10","author":"Rogers","year":"2019","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/nature22393","article-title":"Chemotherapy Drugs Induce Pyroptosis Through Caspase-3 Cleavage of a Gasdermin","volume":"547","author":"Wang","year":"2017","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1055\/s-2003-42639","article-title":"Mechanisms of Hepatocyte Injury, Multiorgan Failure, and Prognostic Criteria in Acute Liver Failure","volume":"23","author":"Riordan","year":"2003","journal-title":"Semin Liver Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djr029","article-title":"Chemopreventative Potential of the Cruciferous Vegetable Constituent Phenethyl Isothiocyanate in a Mouse Model of Prostate Cancer","volume":"103","author":"Powolny","year":"2011","journal-title":"J Natl Cancer Inst"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2011.06.004","article-title":"Biological Targets of Isothiocyanates","volume":"1810","author":"Brown","year":"2011","journal-title":"Biochim Biophys Acta"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3109\/03602532.2015.1058819","article-title":"A Principal Mechanism for the Cancer Chemopreventive Activity of Phenethyl Isothiocyanate is Modulation of Carcinogen Metabolism","volume":"47","author":"Ioannides","year":"2015","journal-title":"Drug Metab Rev"},{"key":"B17","article-title":"Phenethyl Isothiocyanate, a Natural Chemopreventive Agent, Activates C-Jun N-Terminal Kinase 1","volume":"56","author":"Yu","year":"1996","journal-title":"Cancer Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-1545","article-title":"Caspase-Dependent Apoptosis Induction by Phenethyl Isothiocyanate, a Cruciferous Vegetable-Derived Cancer Chemopreventive Agent, is Mediated by Bak and Bax","volume":"11","author":"Xiao","year":"2005","journal-title":"Clin Cancer Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.48","article-title":"Reactivation of Mutant P53 by a Dietary-Related Compound Phenethyl Isothiocyanate Inhibits Tumor Growth","volume":"23","author":"Aggarwal","year":"2016","journal-title":"Cell Death Differ"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3945\/jn.110.121905","article-title":"Candidate Dietary Phytochemicals Modulate Expression of Phase II Enzymes GSTP1 and NQO1 in Human Lung Cells","volume":"140","author":"Tan","year":"2010","journal-title":"J Nutr"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2010.11.005","article-title":"Allyl-, Butyl- and Phenylethyl-Isothiocyanate Activate Nrf2 in Cultured Fibroblasts","volume":"63","author":"Ernst","year":"2011","journal-title":"Pharmacol Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2020.12.021","article-title":"Dietary Isothiocyanates Inhibit Cancer Progression by Modulation of Epigenome","author":"Sundaram","year":"2021","journal-title":"Semin Cancer Biol"},{"key":"B23","article-title":"Chemopreventive Isothiocyanates Induce Apoptosis and Caspase-3-Like Protease Activity","volume":"58","author":"Yu","year":"1998","journal-title":"Cancer Res"},{"key":"B24","article-title":"Essential Role of P53 in Phenethyl Isothiocyanate-Induced Apoptosis","volume":"58","author":"Huang","year":"1998","journal-title":"Cancer Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e140","DOI":"10.1038\/cddis.2011.22","article-title":"Phenethyl Isothiocyanate Exhibits Antileukemic Activity In Vitro and In Vivo by Inactivation of Akt and Activation of JNK Pathways","volume":"2","author":"Gao","year":"2011","journal-title":"Cell Death Dis"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.108239","article-title":"Meisoindigo Attenuates Dextran Sulfate Sodium-Induced Experimental Colitis via Its Inhibition of TAK1 in Macrophages","volume":"101","author":"Wang","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00650","article-title":"Cell-In-Cell Structures in the Liver: A Tale of Four E's","volume":"11","author":"Davies","year":"2020","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15565","article-title":"Autophagy Regulation is an Effective Strategy to Improve the Prognosis of Chemically Induced Acute Liver Injury Based on Experimental Studies","volume":"24","author":"Hu","year":"2020","journal-title":"J Cell Mol Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1540","article-title":"Deficiency of miR-208a Exacerbates CCl4-Induced Acute Liver Injury in Mice by Activating Cell Death Pathways","volume":"4","author":"Bala","year":"2020","journal-title":"Hepatol Commun"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1158\/1535-7163.567.3.5","article-title":"Proteasome-Mediated Degradation of Cell Division Cycle 25C and Cyclin-Dependent Kinase 1 in Phenethyl Isothiocyanate-Induced G2-M-Phase Cell Cycle Arrest in PC-3 Human Prostate Cancer Cells","volume":"3","author":"Xiao","year":"2004","journal-title":"Mol Cancer Ther"},{"key":"B31","doi-asserted-by":"publisher","first-page":"698","DOI":"10.3390\/antiox9080698","article-title":"Phenylethyl Isothiocyanate Extracted From Watercress By-Products With Aqueous Micellar Systems: Development and Optimisation","volume":"9","author":"Coscueta","year":"2020","journal-title":"Antioxidants (Basel)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ab.2003.08.011","article-title":"Determination of Phenethyl Isothiocyanate in Human Plasma and Urine by Ammonia Derivatization and Liquid Chromatography-Tandem Mass Spectrometry","volume":"323","author":"Ji","year":"2003","journal-title":"Anal Biochem"},{"key":"B33","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/s41419-019-1441-4","article-title":"Cleavage of GSDME by Caspase-3 Determines Lobaplatin-Induced Pyroptosis in Colon Cancer Cells","volume":"10","author":"Yu","year":"2019","journal-title":"Cell Death Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.532568","article-title":"Nuclear Factor Erythroid 2 Related Factor 2 Activator JC-5411 Inhibits Atherosclerosis Through Suppression of Inflammation and Regulation of Lipid Metabolism","volume":"11","author":"Jiang","year":"2020","journal-title":"Front Pharmacol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111666","article-title":"Phenethyl Isothiocyanate Attenuates Diabetic Nephropathy via Modulation of Glycative\/Oxidative\/Inflammatory Signaling in Diabetic Rats","volume":"142","author":"Eisa","year":"2021","journal-title":"BioMed Pharmacother"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aat2738","article-title":"Chemical Disruption of the Pyroptotic Pore-Forming Protein Gasdermin D Inhibits Inflammatory Cell Death and Sepsis","volume":"3","author":"Rathkey","year":"2018","journal-title":"Sci Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0669-6","article-title":"FDA-Approved Disulfiram Inhibits Pyroptosis by Blocking Gasdermin D Pore Formation","volume":"21","author":"Hu","year":"2020","journal-title":"Nat Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.825428\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T07:08:53Z","timestamp":1674630533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.825428\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2022.825428"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.825428","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]},"article-number":"825428"}}