Survival and Proliferation of Activated Hepatic Stellate Cells Requires REST

The activation of hepatic stellate cells (HSCs) is a key driver of liver fibrosis and inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD). Targeting activated HSCs has shown promise in preventing liver fibrosis and cancer in mouse models. HSC activation is characterized by increased mitochondrial metabolism and upregulation of pro-fibrotic genes. Since RE1-silencing transcription factor (REST) is known to regulate cell fate, metabolism, and survival, we investigated its involvement in HSC activation. We observed reduced Rest mRNA levels in mouse activated HSCs as compared with mouse quiescent HSCs. In primary human HSCs and HSC-like LX2 cells, REST knock-down led to decreased expression of pro-fibrogenic markers and was essential for the survival and proliferation of activated human HSCs in vitro . REST knock-down also promoted lipid accumulation, impaired mitochondrial metabolism, and increased AMPK phosphorylation and autophagy, resulting in reduced growth. Our findings identify a REST-dependent mechanism of HSC activation that is important for their survival and proliferation.