Therapeutic Targeting of Hepatic Stellate Cell Inactivation and Collagen Degradation by IC-2 Mitigates Liver Fibrosis
- 1Division of Regenerative Medicine and Therapeutics, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8503, Tottori, Japan
- 2KanonCure Inc., Yonago 683-8503, Tottori, Japan
- 3Research Initiative Center, Tottori University, Tottori 680-8550, Tottori, Japan
Abstract
Liver fibrosis, characterized by excessive accumulation of the extracellular matrix (ECM), is caused by an imbalance between fibrogenesis and fibrolysis. Effective antifibrotic therapy requires the regulation of hepatic stellate cells (HSCs) through the production of collagen and matrix metalloproteinases (MMPs). The TGF-β/Smad and Wnt/β-catenin pathways play central roles in this regulation. In this study, we investigated whether IC-2, a Wnt/β-catenin inhibitor derived from ICG-001, reduces TGF-β/Smad and Wnt/β-catenin signaling in HSCs in vitro. We further examined the anti-fibrotic effects in two fibrosis models: carbon tetrachloride (CCl4)-treated mice and high-fat diet (HFD)-fed ob/ob mice. IC-2 markedly suppressed the TGF-β/Smad and Wnt/β-catenin pathway in HSCs. Furthermore, IC-2 markedly ameliorated liver fibrosis in CCl4-treated mice, accompanied with suppressed HSC activation and enhanced collagenolytic activity. IC-2 also attenuated fibrosis in the livers of HFD-fed mice. Co-immunoprecipitation analysis confirmed that IC-2 disrupts the β-catenin/CREB-binding protein (CBP) complex. IC-2 specifically induced MMP-1 expression in human HSCs, while the JNK inhibitor SP600125 suppressed IC-2-mediated MMP-1 induction at 48 h, but not at 24 h. It is suggested that this delayed effect may be due to a delayed transcriptional response or indirect signaling cascade downstream of JNK activation. These findings demonstrate that IC-2 mitigates liver fibrosis by inhibiting HSC activation and promoting collagenolysis, highlighting its therapeutic potential in cirrhosis.
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BibTeX
@article{itaba2026therapeutic,
title = {{Therapeutic Targeting of Hepatic Stellate Cell Inactivation and Collagen Degradation by IC-2 Mitigates Liver Fibrosis}},
author = {Noriko Itaba and Ken-ichiro Abe and Yohei Kono and Hiroki Shimizu and Hiroyuki Oka and Minoru Morimoto and Daisuke Nanba and Goshi Shiota},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219522},
url = {https://www.mdpi.com/1422-0067/27/21/9522},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Therapeutic Targeting of Hepatic Stellate Cell Inactivation and Collagen Degradation by IC-2 Mitigates Liver Fibrosis
AU - Noriko Itaba
AU - Ken-ichiro Abe
AU - Yohei Kono
AU - Hiroki Shimizu
AU - Hiroyuki Oka
AU - Minoru Morimoto
AU - Daisuke Nanba
AU - Goshi Shiota
PY - 2026
DA - 2026/10/24
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219522
UR - https://www.mdpi.com/1422-0067/27/21/9522
AB - Liver fibrosis, characterized by excessive accumulation of the extracellular matrix (ECM), is caused by an imbalance between fibrogenesis and fibrolysis. Effective antifibrotic therapy requires the regulation of hepatic stellate cells (HSCs) through the production of collagen and matrix metalloproteinases (MMPs). The TGF-β/Smad and Wnt/β-catenin pathways play central roles in this regulation. In this study, we investigated whether IC-2, a Wnt/β-catenin inhibitor derived from ICG-001, reduces TGF-β/Smad and Wnt/β-catenin signaling in HSCs in vitro. We further examined the anti-fibrotic effects in two fibrosis models: carbon tetrachloride (CCl4)-treated mice and high-fat diet (HFD)-fed ob/ob mice. IC-2 markedly suppressed the TGF-β/Smad and Wnt/β-catenin pathway in HSCs. Furthermore, IC-2 markedly ameliorated liver fibrosis in CCl4-treated mice, accompanied with suppressed HSC activation and enhanced collagenolytic activity. IC-2 also attenuated fibrosis in the livers of HFD-fed mice. Co-immunoprecipitation analysis confirmed that IC-2 disrupts the β-catenin/CREB-binding protein (CBP) complex. IC-2 specifically induced MMP-1 expression in human HSCs, while the JNK inhibitor SP600125 suppressed IC-2-mediated MMP-1 induction at 48 h, but not at 24 h. It is suggested that this delayed effect may be due to a delayed transcriptional response or indirect signaling cascade downstream of JNK activation. These findings demonstrate that IC-2 mitigates liver fibrosis by inhibiting HSC activation and promoting collagenolysis, highlighting its therapeutic potential in cirrhosis.
SN - 1422-0067
ER -