137 The long-term stasis of blood in the liver, known as chronic liver congestion, can lead to a range of diseases – some of which are fatal. However, identifying how liver congestion causes these diseases has remained unclear, causing difficulty in proposing the best treatment pathway. In a study recently published in Gastroenterology, Japanese researchers have identified a molecular pathway connecting liver congestion to liver fibrosis, portal hypertension, and liver tumourigenesis. This finding has important implications for potential therapies. Chronic liver congestion is also known as congestive hepatopathy, and often progresses to liver fibrosis, eventually cirrhosis, and even cancer. Despite these associations being well-established in the literature for a long time, the specific molecular mechanisms that link liver congestion with liver fibrosis remain relatively unknown. To change this, researchers at The University of Osaka decided to explore these mechanisms to search for potential therapeutic targets that may prevent liver congestion from developing into more severe diseases. “We focused on a type of liver cell called liver sinusoidal endothelial cells, or LSECs, which form the inner lining of the tiny blood vessels inside the liver and are directly affected when blood flow is blocked or slowed, such as during liver congestion,” says lead author, Seiya Kato. “We used state-of-the-art techniques – single-cell and spatial transcriptomics, which allow us to analyse gene activity in individual cells and their locations within tissues – to study liver samples from a mouse model of congestion and from patients with conditions such as Fontan-associated liver disease. This helped us to uncover how liver congestion triggers changes at the molecular level.” These analyses revealed increased activity of two key molecules involved in cell signalling in LSECs: Yes-associated protein (YAP) and connective tissue growth factor (CTGF). Interestingly, the integrin pathway was also observed to be activated in the mouse model of liver congestion. Using LSECs grown in the laboratory, the research team demonstrated that increased hydrostatic pressure (like that which occurs during chronic liver congestion) activates YAP through integrin αV, thereby upregulating CTGF. The team also revealed that inhibiting integrin αV or knocking out CTGF in LSECs leads to improved outcomes in the mouse model of liver congestion. How do these results apply to humans? In single-cell and spatial transcriptomic analyses of liver samples from patients with chronic liver congestion, the researchers found the same pattern that they had seen in mice. YAP was activated in LSECs, leading to increased CTGF levels, and these changes are thought to contribute to disease progression. “Overall, we discovered that a signalling pathway – the integrin αV–YAP–CTGF pathway – in specialised liver blood vessel cells appears to connect liver congestion to fibrosis,” states Hayato Hikita, senior author of the study. “This newly identified pathway could offer a new direction for treatment.” Given that chronic liver congestion can eventually cause serious conditions, such as liver fibrosis, portal hypertension, and liver cancer, these findings may have wide-reaching clinical benefits. Importantly, liver congestion is seen in people with congenital heart disease who have undergone the Fontan procedure, putting them at risk of congestion-related liver damage. Moreover, the increased pressure within the liver’s tiny blood vessels that occurs during chronic liver congestion also happens in liver cirrhosis. This means that the discoveries in this study could help to inform the development of new treatments not only for patients with congestion-related liver disease, but also for those with liver cirrhosis caused by other conditions.