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

Abstract

Background and Purpose This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound. Experimental Approach Rats subjected to bile duct ligation and mice challenged with CCl4 were used to study the antifibrotic effects of COS in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as an in vitro liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)–hairy/enhancer of split‐1 (HES1) pathway was examined using western blot and/or real‐time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation. Key Results In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time‐ and dose‐dependently suppressed the levels of fibrotic markers in LX‐2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3–HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain‐containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation. Conclusions and Implications COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.

Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo

“…Studies also show that CTD inhibits the differentiation and represses hepatic fibrosis by regulating mitogen-activated protein kinases and Notch3 degradation, respectively. Or it suppresses the colon cancer growth by the Wnt/β-Catenin pathway [ 34 – 36 ]. However, our findings suggest that CTD regulates MDM2/p53 interaction by inhibiting AKT activation, which thereby increase apoptosis in cancer cells.…”

The specific PKC-α inhibitor chelerythrine blunts costunolide-induced eryptosis

“…Costunolide possesses anti-angiogenic [9,10] and -osteoarthritic effects [11]. It inhibits pulmonary [12] and hepatic fibrosis [13], induces hair growth [14] and shows strong larvicidal activity [15]. Furthermore, costunolide induces apoptosis, an evolutionary conserved cellular programmed cell death by conjugating with sulfhydryl groups and intracellular thiols, e.g.…”

Prognostic and immunological potential of PPM1G in hepatocellular carcinoma

“…Splicing is expected to be a major source of untapped molecular targets for precision oncology [ 33 ]. PPM1G plays a fundamental role in increasing liver fibrosis by negatively regulating the effect of WWP2 on Notch3 degradation [ 4 ]. More than 80% of hepatocellular carcinoma tumors develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment of the liver [ 3 ].…”

“…Epidemiological research has shown that more than 80% of hepatocellular carcinomas develop in fibrotic or cirrhotic livers [ 3 ]. PPM1G plays a fundamental role in increasing liver fibrosis by negatively regulating the effect of WWP2 on Notch3 degradation [ 4 ]. The inhibition of PPM1G activity by CdCl2 also decreases the protein levels of fibrogenic markers [ 5 ].…”