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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1444100
This article is part of the Research Topic Translational Immunology in End Stage Liver Diseases View all articles

Chitinase 1: A novel therapeutic target in metabolic dysfunctionassociated steatohepatitis

Provisionally accepted
Jung Hoon Cha Jung Hoon Cha 1Na Ri Park Na Ri Park 1*Sung Woo Cho Sung Woo Cho 1Heechul Nam Heechul Nam 1Hyun Yang Hyun Yang 2Eun Sun Jung Eun Sun Jung 3Jeong Won Jang Jeong Won Jang 4Jong Young Choi Jong Young Choi 4Seung Kew Yoon Seung Kew Yoon 4Pil Soo Sung Pil Soo Sung 4*Si Hyun Bae Si Hyun Bae 2*
  • 1 The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
  • 2 Divison of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
  • 3 Department of Hospital Pathology, College of Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
  • 4 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea

The final, formatted version of the article will be published soon.

    Background: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by persistent inflammatory cascades, with macrophage activation playing a pivotal role. Chitinase 1 (CHIT1), produced by activated macrophages, is a key player in this cascade. In this study, we aimed to explore the role of CHIT1 in MASH with progressive liver fibrosis. Methods: Fibrotic liver tissue and serum from distinct patient groups were analyzed using nCounter MAX, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. A MASH mouse model was constructed to evaluate the effectiveness of OATD-01, a chitinase inhibitor. Macrophage profiling was performed using single-nuclei RNA sequencing and flow cytometry. Results: CHIT1 expression in fibrotic liver tissues was significantly correlated with the extent of liver fibrosis, macrophages, and inflammation. Single-nuclei RNA sequencing demonstrated a notable increase in macrophages numbers, particularly of lipid-associated macrophages, in MASH mice. Treatment with OATD-01 reduced non-alcoholic fatty liver disease activity score and Sirius red-positive area. Additionally, OATD-01-treated mice had lower CHIT1, F4/80, and α-smooth muscle actin positivity, as well as significantly lower levels of inflammatory markers, pro-fibrotic genes, and matrix remodeling-related mRNAs than vehicle-treated mice. Although the population of F4/80+CD11b+ intrahepatic mononuclear phagocytes remained unchanged, their infiltration and activation (CHIT1+MerTK+) significantly decreased in OATD-01-treated mice, compared with that observed in vehicle-treated mice. Conclusions: Our study underscores the pivotal role of CHIT1 in MASH. The observed significant improvement in inflammation and hepatic fibrosis, particularly at higher doses of the CHIT1 inhibitor, strongly suggests the potential of CHIT1 as a therapeutic target in MASH accompanied by progressive liver fibrosis

    Keywords: chitinase 1, Mononuclear phagocyte, metabolic dysfunction-associated steatohepatitis, Inflammation, MASH mouse mod

    Received: 05 Jun 2024; Accepted: 09 Sep 2024.

    Copyright: © 2024 Cha, Park, Cho, Nam, Yang, Jung, Jang, Choi, Yoon, Sung and Bae. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Na Ri Park, The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
    Pil Soo Sung, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
    Si Hyun Bae, Divison of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

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