Costunolide represses hepatic fibrosis through WW domain-containing protein 2-mediated Notch3 degradation

Area of Science:

• Pharmacology
• Hepatology
• Molecular Biology

Background:

• Liver fibrosis is a significant health concern characterized by excessive extracellular matrix deposition.
• Natural compounds are being explored for their therapeutic potential in treating liver diseases.
• Costunolide (COS), a sesquiterpene lactone, has demonstrated various biological activities.

Purpose of the Study:

• To investigate the antifibrotic activities of costunolide (COS).
• To elucidate the underlying mechanisms of COS's antifibrotic effects.
• To evaluate COS as a potential therapeutic agent for liver fibrosis.

Main Methods:

• In vivo studies using bile duct ligation (BDL) in rats and CCl4 challenge in mice.
• In vitro studies using primary hepatic stellate cells (pHSCs) and LX-2 cell line.
• Western blot, real-time PCR, immunofluorescence, and co-immunoprecipitation to analyze gene and protein expression and interactions.

Main Results:

• COS administration attenuated liver injury and collagen deposition in vivo.
• COS suppressed fibrotic markers in hepatic stellate cells (HSCs) in a time- and dose-dependent manner.
• COS destabilized Notch3, inhibited the Notch3-HES1 pathway, and blocked the WWP2/PPM1G interaction, promoting Notch3 degradation.

Conclusions:

• Costunolide exhibits significant antifibrotic effects in both in vitro and in vivo models of liver fibrosis.
• COS acts by disrupting the WWP2/PPM1G complex, enhancing Notch3 degradation, and inhibiting the Notch3/HES1 signaling pathway.
• COS represents a potential therapeutic candidate for the treatment of liver fibrosis.