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

Katarzyna Drzewicka¹Katarzyna Głuchowska¹Michal Mlacki¹Bartłomiej Hofman¹Irina Tuszynska¹Tristram Ryan²Katarzyna Piwowar¹Bartosz Wilczyński³Dorota Katarzyna Dymkowska⁴Barbara Dymek¹Tomasz Rejczak¹Kamil Lisiecki¹Adam Gołębiowski¹Adam Jagielski³Angelika Muchowicz¹Dylan Ryan⁵Krzysztof Zabłocki⁴Luke O'Neill⁶Zbigniew Zaslona^1*

• ¹Molecure SA, Warsaw, Poland
• ²Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ³University of Warsaw, Warsaw, Masovian, Poland
• ⁴Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Masovian, Poland
• ⁵University of Cambridge, Cambridge, England, United Kingdom
• ⁶Trinity College Dublin, Dublin, County Dublin, Ireland

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). In this study, we demonstrated the efficacy of OATD-01 in two murine and one rat model 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 marrowderived 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. 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.