{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:14:05Z","timestamp":1783084445198,"version":"3.54.6"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>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-1\u03b2 secretion in BMDMs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1544973","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:13:15Z","timestamp":1748477595000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models"],"prefix":"10.3389","volume":"16","author":[{"given":"Katarzyna","family":"Drzewicka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna M.","family":"G\u0142uchowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Ml\u0105cki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart\u0142omiej","family":"Hofman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Tuszy\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristram A. 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