HMGB1 activates caspase-1 and induces hepatic stellate cell activation via GABPA-ASC.

In the intricate process leading to liver fibrosis, which frequently correlates with inflammation, the activation of hepatic stellate cells (HSCs) is critical. High mobility group box 1(HMGB1), as endogenous danger signal in the extracellular environment, governs the activation of caspase-1 and hepatic stellate cell. Constructing a liver fibrosis model via intraperitoneal thioacetamide (TAA) administration unveiled excessive HMGB1 expression and serum release during the TAA-induced fibrosis progression. Intraperitoneal injection of ethyl pyruvate (EP, which inhibits the release of HMGB1) or AAV-shHMGB1 can significantly reverse the progression of liver fibrosis induced by TAA. Recombinant HMGB1 (rHMGB1) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat HSCs. It was found that HMGB1 could activate caspase-1, while Z-YVAD-FMK could prevent HMGB1-induced activation of HSCs. Through immunofluorescence, immunoblotting, lentiviral transfection, luciferase reporter assay and chromatin immunoprecipitation assay, it was found that HMGB1 activated caspase-1 through GABPA-regulated ASC transcription, which not only participates in the activation of caspase-1, but also promotes the process of liver fibrosis. Taken together, HMGB1 significantly drives HSC activation. It boosts ASC transcriptional activity via GABPA leading to caspase-1 activation and fostering liver fibrosis development.