{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:30:48Z","timestamp":1790674248316,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2016,12,30]],"date-time":"2016-12-30T00:00:00Z","timestamp":1483056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2016,12,30]],"date-time":"2016-12-30T00:00:00Z","timestamp":1483056000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:p>Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin\u2010like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation\u2013 and CCl<jats:sub>4<\/jats:sub>\u2010induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile\u2010acid\u2013induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the <jats:italic toggle=\"yes\">Cxcl1<\/jats:italic> and <jats:italic toggle=\"yes\">Ccl2<\/jats:italic> chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c\u2010Jun, whose cullin\u2010mediated degradation is impaired under these circumstances. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (H<jats:sc>epatology<\/jats:sc> 2017;65:694\u2010709).<\/jats:p>","DOI":"10.1002\/hep.28933","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T23:33:05Z","timestamp":1478561585000},"page":"694-709","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":81,"title":["Deregulated neddylation in liver fibrosis"],"prefix":"10.1097","volume":"65","author":[{"given":"Imanol","family":"Zubiete\u2010Franco","sequence":"first","affiliation":[{"name":"Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd,Derio,Bizkaia,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Fern\u00e1ndez\u2010Tussy","sequence":"additional","affiliation":[{"name":"Center for Cooperative Research in Bioscience (CIC bioGUNE), 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