Statins halt polycystic liver disease by reprogramming metabolism and normalizing mitochondrial bioenergetics in cystic cholangiocytes
Year: 2026
Type: article
Abstract: BACKGROUND AND AIM: Polycystic liver disease (PLD) is a hereditary disorder characterized by the progressive development and enlargement of intrahepatic biliary cysts, which can lead to significant morbidity. Liver transplantation remains the only curative treatment. Mutations in endoplasmic reticulum (ER)-related genes contribute to ER stress in cystic cholangiocytes, promoting disease progression. Given the functional interplay between ER and mitochondria, we investigated mitochondrial dynamics and metabolism in cystic cholangiocytes from both PLD patients and Pkhd1mut rats to identify novel therapeutic targets. APPROACH AND RESULTS: Cystic cholangiocytes exhibited increased mitochondrial mass, membrane potential, and superoxide levels, along with enhanced bioenergetic capacity and ATP production compared with normal cholangiocytes. These alterations were linked to the upregulation of electron transport chain protein complexes. Metabolic reprogramming involved enhanced oxidation of glucose, glutamine, and/or fatty acids, as well as increased denovo cholesterol synthesis and accumulation. Chronic treatment with pravastatin, a cholesterol synthesis inhibitor, significantly reduced hepatomegaly, cyst volume, and fibrosis in Pkhd1mut rats. It also normalized mitochondrial hyperactivity and reduced the proliferation of cystic cholangiocytes in culture, effects that were similarly observed with other statins such as atorvastatin and simvastatin. Importantly, a case-control study in PLD patients showed that statin use was associated with reduced liver growth, further supporting its potential therapeutic role. CONCLUSIONS: Mitochondrial and metabolic dysregulation are central to the pathogenesis of PLD. Targeting cholesterol metabolism with statins represents a promising therapeutic strategy to slow disease progression and reduce cyst burden.
Source: Hepatology
Authors: Enara Markaide, Laura Izquierdo-Sanchez, Irene Olaizola, Josu Urretabizkaia-Garmendia, Mikel Ruiz de Gauna, Xabier Buqué, Irune Lasa-Elosegi, Ainhoa Lapitz, Thomas Bais, Beatriz Val, Pedro M. Rodrigues, Rui E. Castro, Maria J. Perugorria, Luis Bujanda, Ron Gansevoort, Joost P.H. Drenth, Patricia Aspichueta, Jesus M. Banales
Institutions: Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, University of Lisbon, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of the Basque Country, University Medical Center Groningen, University of Groningen, Ikerbasque, Amsterdam University Medical Centers, ERN RARE-LIVER, Universidad de Navarra
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,900
OpenAlex ID: W7128491938