We have previously shown that
adenosine and the
aspartate salt of
adenosine (
IFC305) reverse pre-established CCl(4)-induced
cirrhosis in rats. However, their molecular mechanism of action is not clearly understood. Hepatic stellate cells (HSC) play a pivotal role in liver fibrogenesis leading to
cirrhosis, mainly through their activation, changing from a quiescent adipogenic state to a proliferative myofibrogenic condition. Therefore, we decided to investigate the effect of
IFC305 on primary cultured rat HSC. Our results reveal that this compound suppressed the activation of HSC, as demonstrated by the maintenance of a quiescent cell morphology, including lipid droplets content, inhibition of α-smooth muscle actin (α-SMA) and
collagen α1(I) expression, and up-regulation of MMP-13, Smad7, and PPARγ expression, three key antifibrogenic genes. Furthermore,
IFC305 was able to repress the
platelet-derived growth factor (PDGF)-induced proliferation of HSC. This inhibition was independent of
adenosine receptors stimulation; instead,
IFC305 was incorporated into cells by
adenosine transporters and converted to
AMP by
adenosine kinase. On the other hand, addition of
pyrimidine ribonucleoside as
uridine reversed the suppressive effect of
IFC305 on the proliferation and activation of HSC, suggesting that intracellular
pyrimidine starvation would be involved in the molecular mechanism of action of
IFC305. In conclusion,
IFC305 inhibits HSC activation and maintains their quiescence in vitro; these results could explain in part the antifibrotic liver beneficial effect previously described for this compound on the animal model.