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Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX\u20102 also served as an <jats:italic>in vitro<\/jats:italic> liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)\u2013hairy\/enhancer of split\u20101 (HES1) pathway was examined using western blot and\/or real\u2010time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time\u2010 and dose\u2010dependently suppressed the levels of fibrotic markers in LX\u20102 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3\u2013HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain\u2010containing protein 2 (WWP2)\/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>COS exerted potent antifibrotic effects <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14873","type":"journal-article","created":{"date-parts":[[2019,10,17]],"date-time":"2019-10-17T13:05:06Z","timestamp":1571317506000},"page":"372-387","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Costunolide represses hepatic fibrosis through WW domain\u2010containing protein 2\u2010mediated Notch3 degradation"],"prefix":"10.1111","volume":"177","author":[{"given":"Mao\u2010xu","family":"Ge","sequence":"first","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 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Sichuan Provincial People's Hospital  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong\u2010ke","family":"Yu","sequence":"additional","affiliation":[{"name":"Personalized Drug Therapy Key Laboratory of Sichuan Province Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong\u2010guang","family":"Shao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong\u2010wei","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission 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