Liver international : official journal of the International Association for the Study of the Liver · 2026
Targeting RNA Polymerase I Inhibits Ribosome Biogenesis to Block Liver Fibrosis Progression.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Luo Wei, Yi Lixian, Zhang Yu, Zhou Jing, Li Shihui, Abouelnazar Fatma A, Wang Yanjin, Yan Yongmin
Аннотация
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.
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.