Targeting RNA Polymerase I Inhibits Ribosome Biogenesis to Block Liver Fibrosis Progression

ABSTRACT Background & Aims Liver fibrosis significantly burdens global health, and increased protein synthesis during hepatic stellate cell (HSC) activation plays a crucial role in its progression. Ribosome is the site of protein synthesis. RNA polymerase I (Pol I) is a protein that regulates the transcription of ribosomal DNA (rDNA) genes into ribosomal RNA (rRNA) in ribosomal biogenesis. Therefore, we investigated the role and mechanism of Pol I‐regulated ribosome biogenesis in HSCs activation and liver fibrosis progression. Methods Initially, we assessed the expression levels of Pol I in the serum of patients diagnosed with liver fibrosis. Then, we assessed Pol I‐regulated ribosome biogenesis levels in mouse models of metabolic dysfunction‐associated steatohepatitis (MASH) and carbon tetrachloride (CCl 4 ). Finally, we employed overexpression or knockdown of the Pol I gene in LX2 cells or utilised the Pol I inhibitor CX‐5461 in vivo and in vitro, assessing the levels of ribosome biogenesis and HSCs activation. Results Pol I levels were elevated in the serum of patients with liver fibrosis. Additionally, Pol I‐regulated ribosome biogenesis levels were significantly increased in both MASH and CCl 4 mouse models, as well as in HSCs activated by transforming growth factor beta 1 (TGFβ1). The overexpression of Pol I was found to enhance the activation of HSCs and promote ribosome biogenesis, while the knockdown of Pol I or the inhibitor CX‐5461 inhibited these processes. Conclusions Pol I‐regulated ribosome biogenesis is significantly increased during HSCs activation and liver fibrosis progression. Pol I may serve as a potential target for the diagnosis and treatment of liver fibrosis.