Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models

Seong Hee Kang, Hyung Joon Yim, Ji Won Hwang, Mi Jung Kim, Young Sun Lee, Young Kul Jung, Hyungshin Yim, Baek Hui Kim, Hae Chul Park, Yeon Seok Seo, Ji Hoon Kim, Jong Eun Yeon, Soon Ho Um, Kwan Soo Byun

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Background/Aims: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro-and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions: The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

Original languageEnglish
Pages (from-to)745-756
Number of pages12
JournalKorean Journal of Internal Medicine
Issue number4
Publication statusPublished - 2022
Externally publishedYes


  • Cyclooxygenase 2 inhibitors
  • Hepatic stellate cells
  • Hydroxymethylglutaryl-CoA reductase inhibitors
  • Liver cirrhosis

ASJC Scopus subject areas

  • Internal Medicine


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