Treatment of IL-18-binding protein biologics suppresses fibrotic progression in metabolic dysfunction-associated steatohepatitis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40239621.
- Also identified by DOI 10.1016/j.xcrm.2025.102047 and PMC identifier 12047490.
- Licence recorded as CC BY-NC-ND.
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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.
Medical subject headings
- Liver Cirrhosis
- Intercellular Signaling Peptides and Proteins
- Biological Products
- Fatty Liver