SHP2 inhibitor augments murine liver regeneration via cytoprotective and proproliferative pathway enhancement identified by RNA sequencing

Disruption of the liver’s innate ability to regenerate represents an “undruggable” clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional co-activator which is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent activation of YAP mediated by tyrosine-protein phosphatase non-receptor type 11 (SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. Evaluation of these effects in mice with hepatocyte-specific Yap/Taz deletion demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of non-alcoholic steatohepatitis was associated with improved survival and decreased markers of injury post-hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induce a YAP-dependent pro-proliferative and cytoprotective enhancement of liver regeneration. Murine whole liver lysates mRNA profiles at baseline, 40 hours post-hepatectomy, and 40 hours post-hepatectomy treated with NSC-87877 (15 mg/kg/day)