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 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.

Abstract licence: CC BY-NC-ND

1. 11.

   GSVA: gene set variation analysis for microarray and RNA-Seq data · 2013

2. 15.

   Molecular Pathogenesis of NASH · 2016

3. 30.

   Taurine attenuates arsenic-induced pyroptosis and nonalcoholic steatohepatitis by inhibiting the autophagic-inflammasomal pathway · 2018

4. 43.

   Pyroptosis: mechanisms and diseases · 2021

5. 47.

   Identification of the pyroptosis‑related prognostic gene signature and the associated regulation axis in lung adenocarcinoma · 2021

51 more references, whose wording the paper’s licence keeps private.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.