Exploring the Role of YAP1 and TAZ in Pancreatic Acinar Cells and the Therapeutic Potential of VT-104 in Pancreatic Inflammation

Abstract

ABSTRACTIncreasing evidences have linked the hippo pathway with the fibroinflammatory diseases. We generated a series of genetic knockout mice for targeting the key components of Hippo pathway to examine the individual effects of YAP1 and TAZ on pancreatic inflammation and evaluated the therapeutic potential of the YAP1/TAZ inhibitor VT-104. 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. 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.