{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:39:59Z","timestamp":1790728799159,"version":"4.1.0"},"reference-count":53,"publisher":"American Society for Clinical Investigation","issue":"2","funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["SCHU3146"],"award-info":[{"award-number":["SCHU3146"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 DK113592,UO1AA024206"],"award-info":[{"award-number":["R01 DK113592,UO1AA024206"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Gilead Sciences","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,30]]},"abstract":"<jats:p>\n                    Hepatic inflammasome activation is considered a major contributor to liver fibrosis in NASH. Apoptosis signal\u2013regulating kinase 1 (ASK1) is an apical mitogen-activated protein kinase that activates hepatic JNK and p38 to promote apoptosis, inflammation, and fibrosis. The aim of the current study was to investigate whether pharmacologic inhibition of ASK1 could attenuate hepatic fibrosis driven by inflammasome activation using gain-of-function NOD-like receptor protein 3 (\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    ) mutant mice. Tamoxifen-inducible\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    knock-in (\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    <jats:sup>A350V\/+<\/jats:sup>\n                    CreT-KI) mice and WT mice were administered either control chow diet or diet containing the selective ASK1 inhibitor GS-444217 for 6 weeks. Livers of\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    -KI mice had increased inflammation, cell death, and fibrosis and increased phosphorylation of ASK1, p38, and c-Jun. GS-444217 reduced ASK1 pathway activation, liver cell death, and liver fibrosis. ASK1 inhibition resulted in a significant downregulation of genes involved in collagen production and extracellular matrix deposition, as well as in a reduced hepatic TNF-\u03b1 expression. ASK1 inhibition also directly reduced LPS-induced gene expression of Collagen 1A1 (\n                    <jats:italic>Col1a1<\/jats:italic>\n                    ) in hepatic stellate cells isolated from\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    -KI mice. In conclusion, ASK1 inhibition reduced liver cell death and fibrosis downstream of inflammatory signaling induced by NLRP3. These data provide mechanistic insight into the antifibrotic mechanisms of ASK1 inhibition.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.123294","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T11:01:11Z","timestamp":1580295671000},"source":"Crossref","is-referenced-by-count":74,"title":["ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4780-1844","authenticated-orcid":true,"given":"Susanne","family":"Schuster-Gaul","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UCSD, La Jolla, California, USA."},{"name":"Clinic and Polyclinic for Cardiology, Medical Faculty, Leipzig University, Leipzig, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas Jonathan","family":"Geisler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UCSD, La Jolla, California, USA."},{"name":"Department of Internal Medicine III, RWTH-Aachen University Hospital, Aachen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"McGeough","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UCSD, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey D.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UCSD, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Zagorska","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc., Foster City, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc., Foster City, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Wree","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UCSD, La Jolla, California, USA."},{"name":"Department of Hepatology and Gastroenterology, Charit\u00e9 University Medical Center Berlin, Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Barry","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc., Foster City, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Mikaelian","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc., Foster City, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily J.","family":"Jih","sequence":"additional","affiliation":[{"name":"Department of Pathology, Veterans Affairs San Diego Healthcare System, San Diego, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina G.","family":"Papouchado","sequence":"additional","affiliation":[{"name":"Department of Pathology, Veterans Affairs San Diego Healthcare System, San Diego, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Budas","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc., Foster City, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hal M.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UCSD, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel E.","family":"Feldstein","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, UCSD, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,1,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2013.149"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28431"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2015.10.010"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-016-4095-4"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41395-018-0088-6"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.07.027"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgast-2018-000198"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3109\/07853890.2010.518623"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ni1200"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2012.09.006"},{"key":"B11","doi-asserted-by":"crossref","DOI":"10.1155\/2012\/439587","article-title":"Oxidative Stress-Induced Diseases via the ASK1 Signaling Pathway","volume":"2012","author":"Soga","year":"2012","journal-title":"Int J Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/embo-reports\/kve046"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.42"},{"issue":"1 Pt A","key":"B14","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1016\/j.bbagen.2016.09.028","article-title":"Pleiotropic properties of ASK1","volume":"1861","author":"Sakauchi","year":"2017","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4290"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.02.002"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26592"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006551"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-014-1170-1"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(83)91627-3"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00237-9"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.35953"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(03)00907-7"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2004.40009.x"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.07.019"},{"issue":"4","key":"B26","doi-asserted-by":"crossref","DOI":"10.1038\/nrgastro.2017.21","article-title":"NAFLD: A critical role for the NLRP3 inflammasome in NASH","volume":"14","author":"Thomas","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.01.022"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000022160.64355.62"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17790"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.623280"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.7824938"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.16.3.1247"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29689"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00116-1"},{"issue":"2","key":"B35","first-page":"F85","article-title":"Regulation and function of the JNK subgroup of MAP kinases","volume":"1333","author":"Minden","year":"1997","journal-title":"Biochim Biophys Acta"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201591857"},{"issue":"60","key":"B37","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3001007","article-title":"The role of JNK proteins in metabolism","volume":"2","author":"Vallerie","year":"2010","journal-title":"Sci Transl Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.09.015"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17030281"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28860"},{"issue":"1","key":"B41","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1016\/S0168-8278(17)30301-X","article-title":"Combination of an ASK1 inhibitor and FXR agonist increases efficacy in a mouse model of non-alcoholic steatohepatitis","volume":"66","author":"Liles","year":"2017","journal-title":"J Hepatol"},{"key":"B42","doi-asserted-by":"crossref","first-page":"S399","DOI":"10.1016\/S0168-8278(18)31036-5","article-title":"ACC inhibitor demonstrates potent anti-fibrotic activity in vitro and in vivo","volume":"68","author":"Bates","year":"2018","journal-title":"J Hepatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.05.005"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2002.0597"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101737"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.017"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2001.280.1.L39"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2014-15-2-r29"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/123294\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:19:32Z","timestamp":1779193172000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/123294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,30]]},"references-count":53,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,1,30]]},"published-print":{"date-parts":[[2020,1,30]]}},"alternative-id":["10.1172\/jci.insight.123294"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.123294","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,30]]},"article-number":"e123294"}}