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Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process \u201cprotein polyubiquitination\u201d is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.<\/jats:p>","DOI":"10.3390\/ijms21239043","type":"journal-article","created":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T03:51:16Z","timestamp":1606535476000},"page":"9043","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis"],"prefix":"10.3390","volume":"21","author":[{"given":"Maria","family":"Mercado-G\u00f3mez","sequence":"first","affiliation":[{"name":"Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8452-6939","authenticated-orcid":false,"given":"Fernando","family":"Lopitz-Otsoa","sequence":"additional","affiliation":[{"name":"Precision Medicine and Metabolism Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel","family":"Azkargorta","sequence":"additional","affiliation":[{"name":"Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, ProteoRed-ISCII, 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Serrano-Maci\u00e1","sequence":"additional","affiliation":[{"name":"Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1856-3664","authenticated-orcid":false,"given":"Sofia","family":"Lachiondo-Ortega","sequence":"additional","affiliation":[{"name":"Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naroa","family":"Goikoetxea-Usandizaga","sequence":"additional","affiliation":[{"name":"Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Rodr\u00edguez-Agudo","sequence":"additional","affiliation":[{"name":"Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fern\u00e1ndez-Ramos","sequence":"additional","affiliation":[{"name":"Precision Medicine and Metabolism Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0988-2006","authenticated-orcid":false,"given":"Maider","family":"Bizkarguenaga","sequence":"additional","affiliation":[{"name":"Precision Medicine and Metabolism Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia Guti\u00e9rrez-de","family":"Juan","sequence":"additional","affiliation":[{"name":"Precision Medicine and Metabolism 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Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU), 20014 San Sebastian, Spain"},{"name":"Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1186-6849","authenticated-orcid":false,"given":"Jose J. 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