Treatment of IL-18-binding protein biologics suppresses fibrotic progression in metabolic dysfunction-associated steatohepatitis

  • Cell Rep Med. 2025 Apr 15;6(4):102047. doi: 10.1016/j.xcrm.2025.102047.
Dong-Hyun Kim  1 ,  Gona Choi  1 ,  Eun-Bi Song  1 ,  Hanna Lee  2 ,  Jaehui Kim  3 ,  Young-Saeng Jang  3 ,  JinJoo Park  4 ,  Susan Chi  4 ,  Jaekyu Han  4 ,  Sun-Mi Kim  4 ,  Dongyoon Kim  5 ,  Soo Han Bae  6 ,  Hye Won Lee  7 ,  Jun Yong Park  7 ,  Seung Goo Kang  8 ,  Sang-Hoon Cha  9 ,  Yong-Hyun Han  10
Affiliations
  • 1. Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea.
  • 2. Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea; Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea.
  • 3. Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea; Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea.
  • 4. AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea.
  • 5. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6. Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 7. Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 8. Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea; Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea. Electronic address: [email protected].
  • 9. Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea; AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea. Electronic address: [email protected].
  • 10. Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea; Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea. Electronic address: [email protected].
PMID: 40239621 DOI: 10.1016/j.xcrm.2025.102047
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.

Keywords
APB-R3; IFNγ; IL-18BP; MASH; fibrosis; hepatic stellate cell.
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