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Publications

Journal Article Epublish

PubMed: 40510344 DOI: 10.3389/fimmu.2025.1544973

Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models.

Front Immunol 16:1544973

Authors: Katarzyna Drzewicka, Katarzyna M Głuchowska, Michal Mlącki, Bartłomiej Hofman, Irina Tuszyńska, Tristram A J Ryan, Katarzyna Piwowar, Bartosz Wilczyński, Dorota Dymkowska, Marcin M Grzybowski, Barbara Dymek, Tomasz Rejczak, Kamil Lisiecki, Adam Gołębiowski, Adam Jagielski, Angelika Muchowicz, Dylan Ryan, Krzysztof Zabłocki, Luke A J O'Neill, Zbigniew Zasłona

Affiliations

  • Molecure S.A. Warsaw, Poland.
  • Division of Immunology, Division of Gastroenterology, Harvard Medical School and Boston Children's Hospital, Boston, MA, United States.
  • Institute of Informatics, Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, Poland.
  • Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Warsaw, Poland.
  • Department of Metabolic Regulation, University of Warsaw, Warsaw, Poland.
  • The Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom.
  • School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.

Abstract

Background

OATD-01 is a chitinase-1 (CHIT1) inhibitor, reducing inflammation and fibrosis in animal models where chronic inflammation leads to tissue remodeling. CHIT1, predominantly secreted by macrophages, is overexpressed in metabolic dysfunction-associated steatohepatitis (MASH).

Methods and results

In the study, we demonstrated the therapeutic efficacy of OATD-01 in two murine models (STAM, DIAMOND) and one rat model (CDHFD) of MASH. RNA-Seq analysis of livers obtained from CDHFD rat model revealed that OATD-01 reversed MASH-dysregulated genes. In addition to reducing inflammation and fibrosis observed in the rat model, RNA-Seq demonstrated that OATD-01 regulated key metabolic processes such as acetyl-CoA metabolism, triglyceride metabolism, cholesterol synthesis, cholesterol flux, and glycolysis. Using functional assay performed on bone marrow-derived macrophages (BMDMs) we demonstrated that both genetic and pharmacological inactivation of CHIT1 resulted in inhibition of glucose uptake. As a consequence, our data suggest decreased glycolysis, accompanied by increased ATP levels, lower citrate, and increased acetate levels, ultimately leading to a reduced IL-1β secretion in BMDMs.

Conclusions

These results revealed the key role for CHIT1 in regulating metabolism. OATD-01 is a macrophage modulator that can directly restore metabolic balance and consequently inhibit inflammation and fibrosis, supporting its use for MASH treatment.

MeSH

Fibrosis, Homeostasis, Macrophages, Non-Alcoholic Fatty Liver Disease, Cholesterol, Therapeutics, Chitinases