Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway
Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of l...
| Principais autores: | , , , , , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
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PeerJ Inc.
2022-05-01
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| coleção: | PeerJ |
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| Acesso em linha: | https://peerj.com/articles/13376.pdf |
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| author | Sumin Sun Sheng Huan Zhanghao Li Yue Yao Ying Su Siwei Xia Shijun Wang Xuefen Xu Jiangjuan Shao Zili Zhang Feng Zhang Jinbo Fu Shizhong Zheng |
| author_facet | Sumin Sun Sheng Huan Zhanghao Li Yue Yao Ying Su Siwei Xia Shijun Wang Xuefen Xu Jiangjuan Shao Zili Zhang Feng Zhang Jinbo Fu Shizhong Zheng |
| author_sort | Sumin Sun |
| collection | DOAJ |
| description | Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis. |
| first_indexed | 2024-03-09T08:19:36Z |
| format | Article |
| id | doaj.art-7f1d5752c66643f2bc43e128d0d19481 |
| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T08:19:36Z |
| publishDate | 2022-05-01 |
| publisher | PeerJ Inc. |
| record_format | Article |
| series | PeerJ |
| spelling | doaj.art-7f1d5752c66643f2bc43e128d0d194812023-12-02T21:53:37ZengPeerJ Inc.PeerJ2167-83592022-05-0110e1337610.7717/peerj.13376Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathwaySumin Sun0Sheng Huan1Zhanghao Li2Yue Yao3Ying Su4Siwei Xia5Shijun Wang6Xuefen Xu7Jiangjuan Shao8Zili Zhang9Feng Zhang10Jinbo Fu11Shizhong Zheng12Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Pharmacy, East China University of Science and Technology, Shanghai, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaShandong Co-innovation Center of TCM Formula, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaDepartment of Pharmacy, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, ChinaLiver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis.https://peerj.com/articles/13376.pdfCurcumolNecroptosisER stressSirt1NICDLiver fibrosis |
| spellingShingle | Sumin Sun Sheng Huan Zhanghao Li Yue Yao Ying Su Siwei Xia Shijun Wang Xuefen Xu Jiangjuan Shao Zili Zhang Feng Zhang Jinbo Fu Shizhong Zheng Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway PeerJ Curcumol Necroptosis ER stress Sirt1 NICD Liver fibrosis |
| title | Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway |
| title_full | Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway |
| title_fullStr | Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway |
| title_full_unstemmed | Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway |
| title_short | Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway |
| title_sort | curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress mediated necroptosis of hepatic stellate cells through sirt1 nicd pathway |
| topic | Curcumol Necroptosis ER stress Sirt1 NICD Liver fibrosis |
| url | https://peerj.com/articles/13376.pdf |
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