title: Metformin is a novel suppressor for transforming growth factor (TGF)-β1.
abstract: Metformin is a widely used first-line antidiabetic drug that has been shown to protect against a variety of specific diseases in addition to diabetes, including cardiovascular disorders, polycystic ovary syndrome, and cancer. However, the precise mechanisms underlying the diverse therapeutic effects of metformin remain elusive. Here, we report that transforming growth factor-β1 (TGF-β1), which is involved in the pathogenesis of numerous diseases, is a novel target of metformin. Using a surface plasmon resonance-based assay, we identified the direct binding of metformin to TGF-β1 and found that metformin inhibits [(125)I]-TGF-β1 binding to its receptor. Furthermore, based on molecular docking and molecular dynamics simulations, metformin was predicted to interact with TGF-β1 at its receptor-binding domain. Single-molecule force spectroscopy revealed that metformin reduces the binding probability but not the binding force of TGF-β1 to its type II receptor. Consequently, metformin suppresses type II TGF-β1 receptor dimerization upon exposure to TGF-β1, which is essential for downstream signal transduction. Thus, our results indicate that metformin is a novel TGF-β suppressor with therapeutic potential for numerous diseases in which TGF-β1 hyperfunction is indicated.
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Jianshu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Zhonghe
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Yenan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Nanostructures and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Ruifei
authors.initials: R
authors.lastname: Chen
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Nanostructures and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Fang
authors.affiliation: Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Academy for Advanced Interdisciplinary Studies, Peking University, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D006801:Humans; D008687:Metformin / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D000072417:Protein Domains; D020349:Surface Plasmon Resonance; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D008687:Metformin