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

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Liver fibrosis is a major global health concern.
• Hepatic stellate cell (HSC) activation and increased protein synthesis are key drivers of liver fibrosis.
• Ribosome biogenesis, regulated by RNA polymerase I (Pol I), is crucial for protein synthesis.

Purpose of the Study:

• To investigate the role and mechanism of Pol I-regulated ribosome biogenesis in HSC activation and liver fibrosis progression.

Main Methods:

• Assessed Pol I levels in liver fibrosis patients' serum.
• Evaluated Pol I-regulated ribosome biogenesis in metabolic dysfunction-associated steatohepatitis (MASH) and carbon tetrachloride (CCl4) mouse models.
• Utilized Pol I gene manipulation (overexpression/knockdown) and a Pol I inhibitor (CX-5461) in LX2 cells and in vivo/in vitro models.

Main Results:

• Elevated Pol I levels were observed in the serum of liver fibrosis patients.
• Pol I-regulated ribosome biogenesis was significantly increased in MASH and CCl4 mouse models and activated HSCs.
• Pol I overexpression enhanced HSC activation and ribosome biogenesis, while Pol I inhibition reduced these effects.

Conclusions:

• Pol I-regulated ribosome biogenesis is upregulated during HSC activation and liver fibrosis.
• Pol I represents a potential diagnostic and therapeutic target for liver fibrosis.