Anti-Endoglin monoclonal antibody prevents the progression of liver sinusoidal endothelial inflammation and fibrosis in MASH

Life Sci. 2025 Mar 1:364:123428. doi: 10.1016/j.lfs.2025.123428. Epub 2025 Jan 29.

Abstract

Liver sinusoidal endothelial inflammation/dysfunction and fibrosis are a crucial part of Metabolic Dysfunction Associated Steatohepatitis (MASH) development. TRC105 and M1043 are anti-endoglin (ENG) monoclonal antibodies that bind ENG. In this study, we hypothesized that treatment with anti-ENG antibodies would prevent the progression of LSECs inflammation and fibrosis in vivo and in vitro. MASH was induced in male C57BL/6 mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) for 4 or 8 weeks. In the rescue study, mice were divided into three groups: a control group (chow diet), a MASH group (CDAA-HFD + IgG), and a rescue group (CDAA-HFD + M1043). Later, two groups received rat IgG1 (10 mg/kg) and M1043 (10 mg/kg). In in vitro experiments, inflammation was induced in human LSECs by ox-LDL (50 μg/mL) and treated with TRC105 (300 μg/mL). Liver sinusoidal endothelial inflammation/dysfunction in MASH animals was characterized by endothelial overexpression of ENG, VCAM-1, and ICAM-1 and reduced VE-cadherin and p-eNOS/eNOS expression. M1043 treatment prevented the overexpression of ENG, VCAM-1, and ICAM-1, the progression of liver fibrosis, and the increase of liver-to-body weight ratio. In vitro experiments with TRC105 confirmed the prevention of LSECs inflammation development by reduced ENG and VCAM-1 expression, as well as decreased THP-1 monocytic cell adhesion in ox-LDL activated LSECs. In conclusion, we demonstrate that anti-ENG antibody treatment can prevent LSECs inflammation and fibrosis progression in a MASH animal model and LSECs inflammation in vitro. Thus, we propose directly targeted ENG may represent a promising pharmacological approach for addressing LSECs inflammation and liver fibrosis.

Keywords: Anti-endoglin antibody; Endoglin; Fibrosis; Liver alteration; Liver sinusoidal endothelial inflammation.

MeSH terms

  • Animals
  • Antibodies, Monoclonal* / pharmacology
  • Diet, High-Fat / adverse effects
  • Disease Progression
  • Endoglin* / antagonists & inhibitors
  • Endoglin* / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Humans
  • Inflammation* / drug therapy
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Inflammation* / prevention & control
  • Liver Cirrhosis* / drug therapy
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Liver Cirrhosis* / prevention & control
  • Liver* / drug effects
  • Liver* / metabolism
  • Liver* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Non-alcoholic Fatty Liver Disease / prevention & control
  • Rats

Substances

  • Antibodies, Monoclonal
  • Endoglin