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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Frontiers Media S.A.
2025-05-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Katarzyna Drzewicka |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-51f3f8575d8d4df0a9d31f6b4f32d920 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-51f3f8575d8d4df0a9d31f6b4f32d9202025-08-20T03:36:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15449731544973Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal modelsKatarzyna Drzewicka0Katarzyna M. Głuchowska1Michal Mlącki2Bartłomiej Hofman3Irina Tuszyńska4Tristram A. J. Ryan5Katarzyna Piwowar6Bartosz Wilczyński7Dorota Dymkowska8Marcin M. Grzybowski9Barbara Dymek10Tomasz Rejczak11Kamil Lisiecki12Adam Gołębiowski13Adam Jagielski14Angelika Muchowicz15Dylan Ryan16Krzysztof Zabłocki17Luke A. J. O’Neill18Zbigniew Zasłona19Molecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandDivision of Immunology, Division of Gastroenterology, Harvard Medical School and Boston Children’s Hospital, Boston, MA, United StatesMolecure S.A., Warsaw, PolandInstitute of Informatics, Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw, PolandLaboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Warsaw, PolandMolecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandMolecure S.A., Warsaw, PolandDepartment of Metabolic Regulation, University of Warsaw, Warsaw, PolandMolecure S.A., Warsaw, PolandThe Medical Research Council (MRC) Mitochondrial Biology Unit, University of Cambridge, Cambridge, United KingdomLaboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Warsaw, PolandSchool of Biochemistry and Immunology, Trinity College Dublin, Dublin, IrelandMolecure S.A., Warsaw, PolandBackgroundOATD-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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1544973/fullchitinase 1OATD-01MASHfibrosisinflammationmacrophage |
| spellingShingle | 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 Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models Frontiers in Immunology chitinase 1 OATD-01 MASH fibrosis inflammation macrophage |
| title | Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models |
| title_full | Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models |
| title_fullStr | Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models |
| title_full_unstemmed | Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models |
| title_short | Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models |
| title_sort | chitinase 1 inhibition attenuates metabolic dysregulation and restores homeostasis in mash animal models |
| topic | chitinase 1 OATD-01 MASH fibrosis inflammation macrophage |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1544973/full |
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