Embryonic lethal abnormal vision like 1-stabilized histone deacetylase 6 promotes hepatic stellate cell activation to accelerate liver fibrosis progression through ribosomal protein S5 downregulation.

Objective: Histone deacetylase 6 (HDAC6) has been confirmed to participate in the regulation of liver fibrosis (LF) progression. This study aims to explore the role and mechanism of HDAC6 in the LF process.

Material and methods: Serum samples were collected from liver cirrhosis (LC) patients and normal healthy individuals. Human hepatic stellate cells (HSC; LX-2) were stimulated with transforming growth factor β1 (TGF-β1) to mimic LF cell models. The levels of HDAC6, ribosomal protein S5 (RPS5), embryonic lethal abnormal vision like 1 (ELAVL1), and fibrosis-related markers were determined by quantitative real-time polymerase chain reaction or western blot. Cell proliferation and invasion were detected using cell counting kit 8 assay, 5-ethynyl-2'-deoxyuridine assay, and Transwell assay. The contents of inflammatory factors were examined using enzyme-linked immunosorbent assay. Furthermore, co-immunoprecipitation and RNA immunoprecipitation assays were performed to assess the interaction between HDAC6 and RPS5 or ELAVL1. The effect of ELAVL1 knockdown on HDAC6 mRNA stability was evaluated using Actinomycin D treatment assay.

Results: HDAC6 showed increased expression in LC patients. The knockdown of HDAC6 reduced TGF-β1-induced LX-2 cell proliferation, invasion, fibrosis, and inflammation. Moreover, HDAC6 reduced the acetylation of RPS5, and RPS5 knockdown reversed the inhibition effect of si-HDAC6 on TGF-β1-induced LX-2 cell proliferation, invasion, fibrosis, and inflammation. Meanwhile, ELAVL1 interacted with HDAC6 to stabilize its mRNA, thus inhibiting RPS5 expression.

Conclusion: Our data revealed that ELAVL1-stabilized HDAC6 promoted TGF-β1-induced HSC activation by repressing RPS5 acetylation, thus providing a novel target for alleviating LF progression.