Article date: September 2017
By: Theerut Luangmonkong, Su Suriguga, Emilia Bigaeva, Miriam Boersema, Dorenda Oosterhuis, Koert P Jong, Detlef Schuppan, Henricus A M Mutsaers, Peter Olinga in Volume 174, Issue 18, pages 3107-3117
Background and Purpose
Liver fibrosis is a major cause of liver‐related mortality and, so far, no effective antifibrotic drug is available. Galunisertib, a TGF‐β receptor type I kinase inhibitor, is a potential candidate for the treatment of liver fibrosis. Here, we evaluated the potency of galunisertib in a human ex vivo model of liver fibrosis.
Experimental Approach
Antifibrotic potency and associated mechanisms were studied ex vivo, using both healthy and cirrhotic human precision‐cut liver slices. Fibrosis‐related parameters, both transcriptional and translational level, were assessed after treatment with galunisertib.
Key Results
Galunisertib showed a prominent antifibrotic potency. Phosphorylation of SMAD2 was inhibited, while that of SMAD1 remained unchanged. In healthy and cirrhotic human livers, spontaneous transcription of numerous genes encoding collagens, including collagen type I, α 1, collagen maturation, non‐collageneous extracellular matrix (ECM) components, ECM remodelling and selected ECM receptors was significantly decreased. The reduction of fibrosis‐related transcription was paralleled by a significant inhibition of procollagen I C‐peptide released by both healthy and cirrhotic human liver slices. Moreover, galunisertib showed similar antifibrotic potency in human and rat lives.
Conclusions and Implications
Galunisertib is a drug that deserves to be further investigated for the treatment of liver fibrosis. Inhibition of SMAD2 phosphorylation is probably a central mechanism of action. In addition, blocking the production and maturation of collagens and promoting their degradation are related to the antifibrotic action of galunisertib.
DOI: 10.1111/bph.13945
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