{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:24:04Z","timestamp":1785860644145,"version":"3.56.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB TRR57 P18"],"award-info":[{"award-number":["SFB TRR57 P18"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"European Union's Horizon 2020 Research and Innovation Programme","doi-asserted-by":"publisher","award":["668031"],"award-info":[{"award-number":["668031"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010677","name":"H2020 Health","doi-asserted-by":"publisher","award":["731875"],"award-info":[{"award-number":["731875"]}],"id":[{"id":"10.13039\/100010677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008050","name":"Fundaci\u00f3n Cellex","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p><jats:bold>Background and Aims:<\/jats:bold> Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Groups of 12-week-old <jats:italic>ApoE<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice were fed ad lib for 7\u00a0weeks with a methionine\/choline deficient (MCD) and western diet (WD). After 3\u00a0weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100\u00a0mg\/kg body weight) or vehicle (0.5% carmellose) every day, 5\u00a0days\/week for a further 4\u00a0weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> IFM-514 inhibited IL-1<jats:italic>\u03b2<\/jats:italic> production in mice challenged with 20\u00a0mg\/kg lipopolysaccharide, and in mouse and human inflammatory cells <jats:italic>in vitro<\/jats:italic>. IFM-514 inhibited hepatic inflammation in the <jats:italic>in vivo<\/jats:italic> non-alcoholic steatohepatitis model assessed by H&amp;amp;E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious <jats:italic>in vivo<\/jats:italic> in MDC-fed <jats:italic>ApoE<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed <jats:italic>ApoE<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.<\/jats:p>","DOI":"10.3389\/fmolb.2021.715765","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T16:43:45Z","timestamp":1629909825000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["The Specific NLRP3 Antagonist IFM-514 Decreases Fibrosis and Inflammation in Experimental Murine Non-Alcoholic Steatohepatitis"],"prefix":"10.3389","volume":"8","author":[{"given":"Sandra","family":"Torres","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian J","family":"Brol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Magdaleno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Schierwagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank E.","family":"Uschner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ortiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Tyc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Bachtler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Stunden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Bertheloot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Kitanovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Schrum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Roush","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Franchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Byth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eicke","family":"Latz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonel","family":"Trebicka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"29937","DOI":"10.1074\/jbc.M114.573659","article-title":"Regulation of Lipogenic Gene Expression by Lysine-specific Histone Demethylase-1 (LSD1)","volume":"289","author":"Abdulla","year":"2014","journal-title":"J. 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