Statins halt polycystic liver disease by reprogramming metabolism and normalizing mitochondrial bioenergetics in cystic cholangiocytes

Background & 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 Pkhd1 mut rats to identify novel therapeutic targets. Approach & Results: Cystic cholangiocytes exhibited increased mitochondrial mass, membrane potential, and superoxide levels, along with enhanced bioenergetic capacity and ATP production compared to 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 de novo cholesterol synthesis and accumulation. Chronic treatment with pravastatin, a cholesterol synthesis inhibitor, significantly reduced hepatomegaly, cyst volume, and fibrosis in Pkhd1 mut 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. Conclusion: 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.