S100A6 Regulated by PATZ1 Promotes Liver Fibrosis by Activating Hepatic Stellate Cells

The transition of hepatic stellate cells (HSCs) from a quiescent state to active myofibroblasts plays a pivotal role in the progression of hepatic fibrosis. While S100A6, a member of the S100 protein family, and PATZ1, a transcriptional regulator, are speculated to play crucial roles in the fibrotic process, their specific functions and interactions in the liver fibrosis remain incompletely understood.

C57BL/6 mice were administrated with CCl₄ and high-fat diet to establish the animal models of hepatic fibrosis through mimicking metabolic dysfunction-associated steatohepatitis (MASH). Adenovirus of S100A6-shRNA and HBAAV of PATZ1 were employed to knock down S100A6 and overexpress PATZ1 in mice liver, respectively. PATZ1 overexpression lentivirus vector was used to up-regulate the expression of PATZ1, and RNA interference was used to knock down the expressions of S100A6 and PATZ1 in HSCs. RNA sequencing (RNA-seq), Co-immunoprecipitation Analyses (Co-IP), Electrophoretic Mobility Shift Assay (EMSA), and Chromatin Immunoprecipitation (ChIP) Assay were conducted to explore the interactions between S100A6 and PATZ1.

Analysis of data from the GEO database revealed that PATZ1 expression was significantly decreased in liver cirrhosis patients, negatively correlated with the severity of fibrosis. Overexpression of PATZ1 could inhibit HSCs activation and alleviate liver fibrosis in vivo, as evidenced by downregulated fibrotic markers and decreased fibrotic areas in mice with hepatic fibrosis. Conversely, S100A6 expression was progressively upregulated during liver fibrosis progression, particularly in activated HSCs. Knockdown of S100A6 inhibited HSCs activation and alleviated liver fibrosis both in vitro and in vivo. Mechanistically, RNA-seq analysis suggested PATZ1 negatively regulated S100A6 expression in the activation process of HSCs, and EMSA further confirmed that PATZ1 could binding to the promoter of S100A6 gene.

S100A6 acted as a downstream target of PATZ1 during HSC activation, and PATZ1 could inhibit HSCs activation through suppression the expression of S100A6. PATZ1/S100A6 offered a potential therapeutic target for the therapy of liver fibrosis.