Slow-Release Prostacyclin Agonist-Immersed Sheet Implantation Suppresses Liver Fibrosis via Hippo Signaling Pathway Activation.

Abstract

Aim: Liver cirrhosis is characterized by fibrosis of the liver. No effective treatments are currently available other than liver transplantation. The slow-release version of prostacyclin agonist ONO1301, ONO1301SR, has prolonged effects and lower blood concentrations than its oral form and may be a treatment option for liver fibrosis. However, its effects are unclear and require further investigation.

Methods: We evaluated the antifibrotic effects of ONO1301SR by implanting ONO1301SR-immersed sheets on the liver in a mouse model of chronic liver injury. Samples of the liver tissue were then assessed by histological and biochemical methods. We also investigated the mechanisms underlying the effects of ONO1301 by performing RNA sequencing analyses, and the investigated results were verified in in vitro experiments.

Results: Implantation of an ONO1301SR-immersed sheet significantly improved liver fibrosis. RNA sequencing of liver tissue treated with the ONO1301SR-immersed sheet indicated activation of the Hippo signaling pathway. When ONO1301 was administered to TAA-injured Fa2N-4 hepatocytes and hepatic stellate LX-2 cells, activation of the Hippo signaling pathway was observed in the cells. Furthermore, hepatocytes treated with ONO1301 significantly suppressed hepatic stellate LX-2 cell activation.

Conclusions: Implantation of ONO1301SR-immersed sheets suppresses liver fibrosis via Hippo signaling pathway activation, suggesting that slow-release prostacyclin agonist may have potential as a promising therapeutic option for liver fibrosis.