The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis
Abstract Background To explore the roles of Annexin A2 (ANXA2) on hepatocyte pyroptosis and hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and underlying molecular mechanism. Methods Bioinformatics analyses were performed on transcriptome data of liver tissues from mice and patients with li...
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03692-1 |
| _version_ | 1798044536774066176 |
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| author | Yun Feng Wenhua Li Zhuoya Wang Ruling Zhang Yan Li Lijuan Zang Peiwen Wang Zhenghong Li Yuwei Dong |
| author_facet | Yun Feng Wenhua Li Zhuoya Wang Ruling Zhang Yan Li Lijuan Zang Peiwen Wang Zhenghong Li Yuwei Dong |
| author_sort | Yun Feng |
| collection | DOAJ |
| description | Abstract Background To explore the roles of Annexin A2 (ANXA2) on hepatocyte pyroptosis and hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and underlying molecular mechanism. Methods Bioinformatics analyses were performed on transcriptome data of liver tissues from mice and patients with liver fibrosis for screening the hepatocyte pyroptosis-related differential genes. The in vivo NASH mouse model and in vitro NASH cellular model were established. The expression levels of Anxa2/ANXA2 were quantified. Then, the upstream transcription factor of Anxa2 was screened by ChIP-Seq and experimentally verified. The effects of the p-STAT3/ANXA2 axis on Caspase-1 mediated pyroptosis and fibrosis were explored by in vivo and in vitro experiments. Results Bioinformatics analyses suggested that the expression of Anxa2/ANXA2 was significantly up-regulated in liver tissues of both NASH mice and patients scoring with high pyroptotic activity. Experimental data showed that the ANXA2 expression was positively associated with the development of hepatocyte pyroptosis and fibrosis. As a transcription factor of ANXA2, p-STAT3 can bind to the promoter of Anxa2 and promote its transcription. The inhibition of p-STAT3 can significantly suppress hepatocyte pyroptosis and fibrosis, which was significantly reversed after the over-expression of Anxa2. Caspase-1 was verified as the player of the p-STAT3/ANXA2 axis to promote pyroptosis and fibrosis. By specifically inhibiting Caspase-1, the promotion effect of the p-STAT3/ANXA2 axis on pyroptosis and fibrosis can be significantly weakened. Conclusion The p-STAT3 promoted Anxa2 expression at the transcription level, thus activating the Caspase-1 mediated hepatocyte pyroptosis and fibrosis in NASH. |
| first_indexed | 2024-04-11T23:05:47Z |
| format | Article |
| id | doaj.art-e5ac1992a6d743db91ce1b47697eb489 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-11T23:05:47Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-e5ac1992a6d743db91ce1b47697eb4892022-12-22T03:58:01ZengBMCJournal of Translational Medicine1479-58762022-11-0120111410.1186/s12967-022-03692-1The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitisYun Feng0Wenhua Li1Zhuoya Wang2Ruling Zhang3Yan Li4Lijuan Zang5Peiwen Wang6Zhenghong Li7Yuwei Dong8Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastroenterology, Jiading Branch of Shanghai General Hospital, Shanghai JiaoTong University School of MedicineDepartment of Endoscopy Center, The First Hospital of Hunan University of Chinese MedicineDepartment of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineAbstract Background To explore the roles of Annexin A2 (ANXA2) on hepatocyte pyroptosis and hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and underlying molecular mechanism. Methods Bioinformatics analyses were performed on transcriptome data of liver tissues from mice and patients with liver fibrosis for screening the hepatocyte pyroptosis-related differential genes. The in vivo NASH mouse model and in vitro NASH cellular model were established. The expression levels of Anxa2/ANXA2 were quantified. Then, the upstream transcription factor of Anxa2 was screened by ChIP-Seq and experimentally verified. The effects of the p-STAT3/ANXA2 axis on Caspase-1 mediated pyroptosis and fibrosis were explored by in vivo and in vitro experiments. Results Bioinformatics analyses suggested that the expression of Anxa2/ANXA2 was significantly up-regulated in liver tissues of both NASH mice and patients scoring with high pyroptotic activity. Experimental data showed that the ANXA2 expression was positively associated with the development of hepatocyte pyroptosis and fibrosis. As a transcription factor of ANXA2, p-STAT3 can bind to the promoter of Anxa2 and promote its transcription. The inhibition of p-STAT3 can significantly suppress hepatocyte pyroptosis and fibrosis, which was significantly reversed after the over-expression of Anxa2. Caspase-1 was verified as the player of the p-STAT3/ANXA2 axis to promote pyroptosis and fibrosis. By specifically inhibiting Caspase-1, the promotion effect of the p-STAT3/ANXA2 axis on pyroptosis and fibrosis can be significantly weakened. Conclusion The p-STAT3 promoted Anxa2 expression at the transcription level, thus activating the Caspase-1 mediated hepatocyte pyroptosis and fibrosis in NASH.https://doi.org/10.1186/s12967-022-03692-1p-STAT3ANXA2Caspase-1PyroptosisNASHHepatic fibrosis |
| spellingShingle | Yun Feng Wenhua Li Zhuoya Wang Ruling Zhang Yan Li Lijuan Zang Peiwen Wang Zhenghong Li Yuwei Dong The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis Journal of Translational Medicine p-STAT3 ANXA2 Caspase-1 Pyroptosis NASH Hepatic fibrosis |
| title | The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis |
| title_full | The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis |
| title_fullStr | The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis |
| title_full_unstemmed | The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis |
| title_short | The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis |
| title_sort | p stat3 anxa2 axis promotes caspase 1 mediated hepatocyte pyroptosis in non alcoholic steatohepatitis |
| topic | p-STAT3 ANXA2 Caspase-1 Pyroptosis NASH Hepatic fibrosis |
| url | https://doi.org/10.1186/s12967-022-03692-1 |
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