The Combination of Sinusoidal Perfusion Enhancement and Apoptosis Inhibition by Riociguat Plus a Galactose-PEGylated Bilirubin Multiplexing Nanomedicine Ameliorates Liver Fibrosis Progression

Chronic liver injury and continuous wound healing lead to extracellular matrix (ECM) deposition and liver fibrosis. The elevated production of reactive oxygen species (ROS) in the liver leads to the apoptosis of hepatocytes and the activation of hepatic stellate cells (HSCs). In the current study, we describe a combination strategy of sinusoidal perfusion enhancement and apoptosis inhibition enabled by riociguat together with a tailor designed galactose-PEGylated bilirubin nanomedicine (Sel@ GBRNPs). Riociguat enhanced sinusoidal perfusion and decreased the associated ROS accumulation and inflammatory state of the fibrotic liver. Concurrently, hepatocyte-targeting galactosePEGylated bilirubin scavenged excessive ROS and released encapsulated selonsertib. The released selonsertib inhibited apoptosis signal-regulating kinase 1 (ASK1) phosphorylation to alleviate apoptosis in hepatocytes. The combined effects on ROS and hepatocyte apoptosis attenuated the stimulation of HSC activation and ECM deposition in a mouse model of liver fibrosis. This work provides a novel strategy for liver fibrosis treatment based on sinusoidal perfusion enhancement and apoptosis inhibition.

Automated summary

This study demonstrates a combination strategy of sinusoidal perfusion enhancement and apoptosis inhibition for liver fibrosis treatment. By using riociguat and a tailor-designed galactose-PEGylated bilirubin nanomedicine, the researchers were able to enhance sinusoidal perfusion, decrease ROS accumulation and inflammation, scavenge excessive ROS, and inhibit apoptosis in hepatocytes. These effects attenuated the activation of hepatic stellate cells and extracellular matrix deposition in a mouse model of liver fibrosis.