Exploring the role of YAP1 and TAZ in pancreatic acinar cells and the therapeutic potential of VT-104 in pancreatic inflammation

Background: Increasing evidence has linked the Hippo pathway with the fibroinflammatory diseases. However, the detailed roles of key hippo components in pancreatic inflammatory diseases still remain unclear. Methods: A series of genetic knockout mice were generated targeting the key components of Hippo pathway to examine the individual effects of YAP1 and TAZ on pancreatic inflammation. Hematoxylin and eosin (H&E) staining, immunohistochemistry, and immunofluorescence staining were performed to evaluate the pancreas tissue from mice with various genotypes. The therapeutic potential of a recently developed YAP1/TAZ inhibitor VT-104 was also evaluated in our mouse model. Results: Mice with acinar-specific knockout of YAP1/TAZ did not exhibit any histological abnormalities in the pancreas. LATS1/2 deficiency induced acinar to ductal metaplasia, immune cell infiltration, and fibroblast activation, which were rescued by the homozygous knockout YAP1, but not TAZ. Additionally, treatment with VT-104 also decreased pathological alterations induced by deletions of LATS1 and LATS2 in acinar cells. Conclusion: Our findings highlight the critical role of YAP1 in modulating pancreatic inflammation and demonstrate that VT-104 holds therapeutic potential to mitigate pancreatitis-associated pathological manifestations. Further exploration is necessary to unravel the underlying mechanisms and translate these insights into clinical applications.