95 Quick summary: Research published in Nature Metabolism has identified that biliary epithelial cells act as active guardians of liver health by utilising a specific protein signalling pathway to maintain a waterproof barrier against scarring. When this regulatory mechanism fails, bile acids leak into liver tissue and trigger the progressive fibrosis that leads to cirrhosis and potentially fatal liver cancer. These findings are critical for public policy and healthcare practice as they explain why certain existing treatments may inadvertently worsen patient outcomes, paving the way for personalised therapies that significantly improve long term well being. Many liver diseases share a common characteristic: fibrosis, that is, the progressive accumulation of scarring in the liver tissue. Those scars – the liver’s response to persistent injuries or attacks – can prevent the organ from functioning properly. Fibrosis affects millions of people worldwide and is a decisive step in the progression towards cirrhosis, a potentially fatal condition that can develop into liver cancer. Now, a new study by the National Cancer Research Centre (CNIO), published in Nature Metabolism, has identified a key mechanism in the development of liver fibrosis. This finding represents a further step towards the development of personalised therapies which help prevent its progression. Nabil Djouder, head of the CNIO Growth Factors, Nutrients and Cancer Group, and his team have focused their research on the bile ducts, which pipe bile through the liver. More specifically, they have studied the cells that form those pathways, called biliary epithelial cells (BEC). Until now, BECs were considered a reservoir of cells capable of regenerating the liver, as well as being the building blocks of the bile ducts – sort of sealed “pipes” that transport bile and prevent it from coming into contact with liver tissue. This study changes that perspective. BEC cells are not just passive tubes but active guardians that regulate the liver’s environment. The new study by CNIO has identified the molecular mechanism that helps bile ducts avoid fibrosis. Under normal conditions, a protein, the FXR receptor, is expressed inside BEC cells. When bile circulates through the bile ducts, FXR detects bile acids, binds to them and activates the production of another protein called YAP. Adhesion molecules then form, which keep the BEC cells so closely joined together that bile cannot reach the liver tissue. At the same time, YAP limits the excessive proliferation of BEC cells, as it regulates the activation of a third protein essential for their multiplication. This system is key for the bile ducts to function as an effective barrier. However, in certain diseases or genetic conditions, the FXR protein stops working properly or is even no longer expressed, resulting in BEC cells losing this control mechanism: they proliferate excessively, the barrier weakens, and bile acids leak into the tissue that performs the liver’s functions — the liver parenchyma. Upon reaching areas of the liver where they should not be, bile acids activate other cells – stellate cells – which generate scars. If these accumulate, they lead to liver fibrosis. Both excessive proliferation of BEC cells and fibrosis can progress to liver cirrhosis, a serious and potentially fatal disease. Paula Sánchez, researcher at Djouder’s team and first author of the study, considers that this work changes our way of understanding the role of bile ducts and highlights the clinical significance of the results: “Our work shows that BEC cells are active regulators of liver health. By controlling FXR-YAP signalling, these cells form a barrier that prevents bile acid leakage and fibrosis. This finding allows us to steer research towards safer and more targeted therapies.” With a combination of animal models – including the first genetic mouse model for cirrhosis, developed previously by Djouder’s group – computational analysis and human liver samples, the team has demonstrated that when FXR receptors are lost in BEC cells, the progression from fibrosis to cirrhosis is accelerated. This knowledge can help establish screenings to select patients for targeted drugs. According to Djouder, “understanding how different types of liver cells respond will allow for better selection of patients suited for FXR-targeted therapies and prevent potential adverse effects in other patients.” The findings of this study help to explain the side effects observed in a drug used to treat liver disease, obeticholic acid (OCA). This drug is a second-line treatment – prescribed when the most common treatment fails – for diseases such as primary biliary cholangitis, which predominantly affects women. OCA is a semisynthetic bile acid designed to activate the FXR receptor in order to treat chronic liver diseases associated with fibrosis. However, in some patients, fibrosis has been seen to worsen after this drug is administered. This study demonstrates that this effect could be related to a dysfunction of FXR in the BEC cells of these patients, which would alter the expected response to the drug. Djouder emphasises that “OCA could worsen fibrosis when FXR signalling is lost in BEC cells. That explains why some patients may experience accelerated liver fibrosis, despite being under treatment.” Faced with these undesirable effects, the US regulatory agency for medications, the FDA, issued a warning about the use of OCA, and it was withdrawn from the US market. In Europe, the European Medicines Agency recommended to the European Commission in 2024 to revoke the authorisation for its sale, but the European Court of Justice allowed it to continue being administered to patients who were already receiving it.