Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models Graphical abstract A B SAMe Autophagy Compensatory activation Accumulation of mis/unfolded proteins Apoptosis SAMe Insufficient compensation Proteasomal activity Proliferation Ciliogenesis un/misfolded proteins (cellular stress) Proteasomal activity Proliferation Ciliogenesis un/misfolded proteins (cellular stress) Survival Cystogenesis PLD SUMOylation PLD SUMOylation Survival Cystogenesis Phenotype Differentiated Phenotype Differentiated Dedifferentiated Dedifferentiated Highlights  PTM abnormalities govern the pathogenesis of polycystic liver disease.  Cystic cholangiocytes show increased UBC9-dependent protein SUMOylation.  SUMOylation exerts adaptive protein dynamics and pro- survival mechanisms.  Targeting of UBC9 with SAMe attenuates hepatic cysto- genesis and fibrosis.  SAMe arises as a promising therapeutic agent for patients with PLD. Authors Pui Y. Lee-Law, Paula Olaizola, Francisco J. Caballero-Camino, ., Luis Bujanda, Joost P.H. Drenth, Jesus M. Banales Correspondence jesus.banales@biodonostia.org (J.M. Banales). Lay summary Protein SUMOylation is a dynamic post- translational event implicated in numerous cellular processes. This study revealed dysre- gulated protein SUMOylation in polycystic liver disease, which promotes hepatic cystogenesis. Administration of S-adeno- sylmethionine (SAMe), a natural UBC9- dependent SUMOylation inhibitor, halted pol- ycystic liver disease in experimental models, thus representing a potential therapeutic agent for patients. Research Article Experimental and Translational Hepatology https://doi.org/10.1016/j.jhep.2020.09.010 © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). J. Hepatol. 2021, 74, 394–406