The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis

Journal of Translational Medicine

卷:20

Research

Zhuoya Wang¹  Wenhua Li²  Peiwen Wang³  Yan Li³  Yuwei Dong³  Yun Feng³  Ruling Zhang³  Zhenghong Li⁴  Lijuan Zang⁵ 

[1] Department of Endoscopy Center, The First Hospital of Hunan University of Chinese Medicine, 95 middle Shaoshan Road, Yuhua District, Changsha City, Hunan Province, China;

[2] Department of Gastroenterology, Jiading Branch of Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, 800 Huangjiahuayuan Road, 201803, Shanghai, China;

[3] Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Hongkou District, 200080, Shanghai, China;

[4] Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665 Konngjiang Road, Hongkou District, 200092, Shanghai, China;

[5] Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, 200080, Shanghai, China;

关键词: p-STAT3;    ANXA2;    Caspase-1;    Pyroptosis;    NASH;    Hepatic fibrosis;   

DOI  :  10.1186/s12967-022-03692-1

 received in 2022-06-14, accepted in 2022-10-06,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundTo explore the roles of Annexin A2 (ANXA2) on hepatocyte pyroptosis and hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and underlying molecular mechanism.MethodsBioinformatics 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.ResultsBioinformatics 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.ConclusionThe p-STAT3 promoted Anxa2 expression at the transcription level, thus activating the Caspase-1 mediated hepatocyte pyroptosis and fibrosis in NASH.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

Fig. 2

13638_2023_2232_Article_IEq196.gif

Fig. 1

13638_2023_2232_Article_IEq184.gif

Fig. 2

Fig. 5

Fig. 9

40507_2023_167_Article_IEq567.gif

13638_2023_2232_Article_IEq92.gif

Fig. 7

13638_2023_2232_Article_IEq78.gif