Inhibition of chloride intracellular channel protein 1 (CLIC1) ameliorates liver fibrosis phenotype by activating the Ca 2+ -dependent Nrf2 pathway.

Autor: Ko M; Chemical Genomics Leader Research Lab, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea., Jung HY; R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea; School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea., Lee D; R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea., Jeon J; R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea., Kim J; Chemical Genomics Leader Research Lab, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea., Baek S; R&D Center, NovMetaPharma Co., Ltd., Pohang 37668, Republic of Korea., Lee JY; Research Center of Bioconvergence Analysis, Korea Basic Science Institute, Ochang 28119, Republic of Korea; Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea., Kim JY; Research Center of Bioconvergence Analysis, Korea Basic Science Institute, Ochang 28119, Republic of Korea; Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea., Kwon HJ; Chemical Genomics Leader Research Lab, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea. Electronic address: kwonhj@yonsei.ac.kr.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Dec; Vol. 168, pp. 115776. Date of Electronic Publication: 2023 Nov 02.
DOI: 10.1016/j.biopha.2023.115776
Abstrakt: Persistent damage to liver cells leads to liver fibrosis, which is characterized by the accumulation of scar tissue in the liver, ultimately leading to cirrhosis and serious complications. Because it is difficult to reverse cirrhosis once it has progressed, the primary focus has been on preventing the progression of liver fibrosis. However, studies on therapeutic agents for liver fibrosis are still lacking. Here, we investigated that the natural dipeptide cyclic histidine-proline (CHP, also known as diketopiperazine) shows promising potential as a therapeutic agent in models of liver injury by inhibiting the progression of fibrosis through activation of the Nrf2 pathway. To elucidate the underlying biological mechanism of CHP, we used the Cellular Thermal Shift Assay (CETSA)-LC-MS/MS, a label-free compound-based target identification platform. Chloride intracellular channel protein 1 (CLIC1) was identified as a target whose thermal stability is increased by CHP treatment. We analyzed the direct interaction of CHP with CLIC1 which revealed a potential interaction between CHP and the E228 residue of CLIC1. Biological validation experiments showed that knockdown of CLIC1 mimicked the antioxidant effect of CHP. Further investigation using a mouse model of CCl 4 -induced liver fibrosis in wild-type and CLIC1 KO mice revealed the critical involvement of CLIC1 in mediating the effects of CHP. Taken together, our results provide evidence that CHP exerts its anti-fibrotic effects through specific binding to CLIC1. These insights into the mechanism of action of CHP may pave the way for the development of novel therapeutic strategies for fibrosis-related diseases.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.L., J.J., and S.B. are employees of NovMetaPharma. H.-Y. J. is board member of NovMetaPhama.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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