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

  • Liver Int. 2026 Jan;46(1):e70478. doi: 10.1111/liv.70478.
Wei Luo  1  2 ,  Lixian Yi  3 ,  Yu Zhang  1  2 ,  Jing Zhou  1  2 ,  Shihui Li  1  2 ,  Fatma A Abouelnazar  4 ,  Yanjin Wang  4 ,  Yongmin Yan  1  2  3
Affiliations
  • 1. Changzhou Key Laboratory of Exosome Basics and Translational Applications, Wujin Hospital Affiliated With Jiangsu University, Changzhou, China.
  • 2. Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, China.
  • 3. Department of Medical Technology, Suzhou Vocational Health College, Suzhou, Jiangsu, China.
  • 4. Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, China.
PMID: 41388799 DOI: 10.1111/liv.70478
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 (CCl4). 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 CCl4 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.

Keywords
HSC activation; liver fibrosis; pol I; rRNA; ribosome biogenesis.
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