Hemichannels (HCs) are essential components of gap junctions, which connect the cytoplasm of neighboring cells. Accumulating evidence suggests that HCs also form a communication pathway, albeit between the cytoplasm and extracellular environment. Transmembrane connexin (Cx) and pannexin (Panx) proteins are the building stones of HCs. In the liver, hepatocytes typically express Cx32, though in several liver pathologies, including liver fibrosis, they switch to a Cx43-based mode. Moreover, a number of recent studies suggest prominent functions for Cx43- and Panx1-based HCs in cell death and inflammatory responses in liver disease. The current project aims at the elucidation of the role of Cx43- and Panx1-based signaling in cell death and inflammation in the context of liver fibrosis. First, expression levels of Cx43 and Panx1 as well as their channel activities will be studied in liver tissue of an animal model of liver fibrosis. Secondly, specific inhibitors of Cx43- and Panx1- based HCs will be tested in relevant liver-based in vitro models for their specificity and their potential to suppress cell death and inflammation. Thirdly, the in vitro findings will be evaluated in vivo in combination with the monitoring of clinical read-outs of liver fibrosis. Overall, this project, which combines fundamental with translational research, is considered of high clinical relevance, as it may introduce an innovative strategy for the diagnosis and treatment of liver fibrosis.