YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

Blog Article

Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC).Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis.YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment.Increased or decreased YAP activity reprograms Organic Black Seed with Vitamin C subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation.Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model.

Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations.Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs Top Console Cap as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.