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

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

BackgroundOATD-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 resul...

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Main 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
Format: Article
Language:English
Published: Frontiers Media S.A. 2025-05-01
Series:Frontiers in Immunology
Subjects:
chitinase 1
OATD-01
MASH
fibrosis
inflammation
macrophage
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2025.1544973/full
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Summary:BackgroundOATD-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 resultsIn 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.ConclusionsThese 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.
ISSN:1664-3224

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