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

作者：Dong-Hyun Kim, Gi Hong Choi, Eun-Bi Song, Han Na Lee, Jae Kyeom Kim, Young‐Saeng Jang, JinJoo Park, Susan Chi, Jaekyu Han, Sun-Mi Kim, Dongyoon Kim, Soo Han Bae, Hye Won Lee, Jun Yong Park, Seung Goo Kang, Sang-Hoon Cha, Yong‐Hyun Han · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.102047 · 被引用次数：9 · 研究领域：Liver Disease Diagnosis and Treatment、Pancreatitis Pathology and Treatment、Liver Diseases and Immunity

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. • The amounts of free IL-18 are increased in MASH despite the enhancement of IL-18BP protein • Overwhelmed IL-18 signaling exacerbates hepatic inflammation and fibrosis • The engineered IL-18BP biologics inhibits MASH via blockade of IFN signaling • IL-18BP biologics suppresses hepatic fibrosis in MASH through HSC inactivation Kim et al. discover that IL-18BP is a key modulator of hepatic inflammation and fibrosis in MASH. The engineered long-...