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Cell Rep. Med., April 15, 2025 | https://doi.org/10.1016/j.xcrm.2025.102047
Treatment of IL-18-binding protein biologics suppresses fibrotic progression in metabolic dysfunction-associated steatohepatitis
Dong-Hyun Kim,1,9 Gona Choi,1,9 Eun-Bi Song,1,9 Hanna Lee,1,2,9 Jaehui Kim,3,4,9 Young-Saeng Jang,3,4 JinJoo Park,5 Susan Chi,5 Jaekyu Han,5 Sun-Mi Kim,5 Dongyoon Kim,6 Soo Han Bae,7 Hye Won Lee,8 Jun Yong Park,8 Seung Goo Kang,3,4,* Sang-Hoon Cha,4,5,* and Yong-Hyun Han 1,2,10,*
1Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
2Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea
3Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea
4Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea
5AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea
6Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
7Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, South Korea
8Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea
9These authors contributed equally
10Lead contact
2Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea
3Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea
4Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea
5AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea
6Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
7Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, South Korea
8Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea
9These authors contributed equally
10Lead contact
*Corresponding authors: correspondence to Seung Goo Kang, Sang-Hoon Cha or Yong-Hyun Han
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by inflammation and fibrosis, with enhanced interleukin-18 (IL-18) signaling. IL-18-binding protein (IL-18BP) neutralizes IL-18, but its therapeutic potential in MASH is unclear. We find elevated IL-18BP and IL-18 levels in patients with MASH and mice, with free IL-18 correlating with disease severity. IL-18 stimulates interferon-gamma (IFNγ) production in CD4 T cells, increasing hepatic IL-18BP. IL-18BP-deficient mice show worsened liver inflammation and fibrosis. We develop a human IL-18BP biologics (APB-R3) and inject it to mice to evaluate its pharmacologic efficacy. APB-R3 significantly improves MASH in reducing fibrosis and inflammation and inhibits hepatic stellate cell activation via the cGMP pathway. This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis, and our engineered IL-18BP biologics can become a promising therapeutic candidate for curing MASH.
논문정보
- Research article
- 2025년 04월 (BRIC 등록일 2025-04-17)
- 국내 연구진
- 의약학 > 면역의학
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