Saffron and Calculus bovis combination exerts anti-hepatic fibrotic effect in liver fibrosis rats via the mitogen-activated protein kinases pathway

Abstract

BACKGROUND

Liver fibrosis is a global health issue that lacks effective treatments. Tibetan medicine, with a long history, has accumulated rich experience in the treatment of chronic liver diseases. The saffron (Saf) and Calculus bovis (Cal b) combination is among the most commonly used medicines in clinical practice in Tibetan medicine for hepatic disease. Its characteristic therapies and drug compatibility provide unique ideas for the treatment of liver fibrosis and have research value and application potential.

AIM

To investigate the efficacy of the Saf-Cal b therapy in treating liver fibrosis and explored its underlying mechanism.

METHODS

We initially established a carbon tetrachloride-induced rat liver fibrosis model to assess Saf-Cal b’s anti-fibrotic effects. Subsequently, we conducted network pharmacology analysis to identify the potential therapeutic targets and pathways of Saf-Cal b in liver fibrosis intervention. Finally, we performed in vivo validation of key regulatory targets.

RESULTS

Saf-Cal b combination therapy exerted superior effects in ameliorating liver fibrosis in model rats compared with Saf or Cal b monotherapy. Through network pharmacology prediction, key targets of the combination were identified. Mechanistic validation revealed that Saf-Cal b inhibited the p38 mitogen-activated protein kinases pathway, which in turn suppressed the transforming growth factor-β/small mother against decapentaplegic pathway. This sequential inhibition led to reduced activation of hepatic stellate cells, a central event in liver fibrosis progression.

CONCLUSION

These findings demonstrate that Saf-Cal b combination therapy is more effective than either monotherapy in alleviating liver fibrosis, with its therapeutic effect mediated through the p38 mitogen-activated protein kinases/transforming growth factor-β/small mother against decapentaplegic signaling axis, providing a potential therapeutic strategy for liver fibrosis.

Keywords: Liver fibrosis; Tibetan medicine; Saffron; Calculus bovis; Mitogen-activated protein kinases pathway

Core Tip: Liver fibrosis, a health issue of global concern, lacks effective treatments. Using Tibetan medicine experience and network pharmacology, this study explored the potential mechanism of the saffron-Calculus bovis combination against liver fibrosis in rats. After CCl₄ induction of rats, intragastric intervention was performed, followed by assessments of liver pathology, liver function, inflammation, and hepatic stellate cell activation. The results showed that the combination exerted more significant anti-fibrotic effects compared with single treatment, and it may act by regulating the mitogen-activated protein kinase pathway.