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ACS Central Science

ACS Central Science

IF: 12.7
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Chlorquinaldol Alleviates Lung Fibrosis in Mice by Inhibiting Fibroblast Activation through Targeting Methionine Synthase Reductase

Published:28 August 2024 DOI: 10.1021/acscentsci.4c00798
Xiangyu Yang, Geng Lin, Yitong Chen, Xueping Lei, Yitao Ou, Yuyun Yan, Ruiwen Wu, Jie Yang, Yiming Luo, Lixin Zhao, Xiuxiu Zhang, Zhongjin Yang, Aiping Qin, Ping Sun, Xi-Yong Yu, Wenhui Hu

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Thus, it is essential to investigate potential druggable targets to improve IPF treatment outcomes. By screening a curated library of 201 small molecules, we have identified chlorquinaldol, a known antimicrobial drug, as a potential antifibrotic agent. Functional analyses have demonstrated that chlorquinaldol effectively inhibits the transition of fibroblasts to myofibroblasts in vitro and mitigates bleomycin-induced pulmonary fibrosis in mice. Using a mass spectrometry-based drug affinity responsive target stability strategy, we revealed that chlorquinaldol inhibited fibroblast activation by directly targeting methionine synthase reductase (MTRR). Decreased MTRR expression was associated with IPF patients, and its reduced expression in vitro promoted extracellular matrix deposition. Mechanistically, chlorquinaldol bound to the valine residue (Val-467) in MTRR, activating the MTRR-mediated methionine cycle. This led to increased production of methionine and s-adenosylmethionine, counteracting the fibrotic effect. In conclusion, our findings suggest that chlorquinaldol may serve as a novel antifibrotic medication, with MTRR-mediated methionine metabolism playing a critical role in IPF development. Therefore, targeting MTRR holds promise as a therapeutic strategy for pulmonary fibrosis.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
beta-nadph tetra(cyclohexylammonium) salt 100929-71-3 C27H43N8O17P3 132 suppliers $27.00-$2021.25
beta-nadph tetra(cyclohexylammonium) salt 100929-71-3 C27H43N8O17P3 132 suppliers $27.00-$2021.25
beta-nadph tetra(cyclohexylammonium) salt 100929-71-3 C27H43N8O17P3 132 suppliers $27.00-$2021.25
beta-nadph tetra(cyclohexylammonium) salt 100929-71-3 C27H43N8O17P3 132 suppliers $27.00-$2021.25

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