Abstract
Hepatic stellate cell (HSC) activation is the key process in hepatic fibrosis (HF) development. Targeted death of HSCs could be effective in the prevention and treatment of HF. Phosphatidylethanolamine-binding protein (PEBP)1 can trigger ferroptosis by mediating peroxide production, but how it modulates HSC ferroptosis is not known. We screened natural small molecules that could bind with PEBP1, and investigated the mechanism by which it promotes HSC ferroptosis. The maximum binding energy of berberine with PEBP1 was − 8.51 kcal/mol, indicating that berberine could bind strongly with PEBP1. Berberine binding to PEBP1 could promote HSC ferroptosis via synergy of its actions with those of sorafenib, but it could not induce ferroptosis alone. Combined administration of berberine enhanced the ferroptotic effects of low-dose sorafenib upon HSCs. Herein, we revealed that PEBP1 might be a target that could enhance the effects of sorafenib, which could provide a new therapeutic approach for HF treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abou-Alfa GK et al (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. https://doi.org/10.1200/JCO.2005.01.3441
Azad AI et al (2020) Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis. Hepatology. https://doi.org/10.1002/hep.31211
Baghaei K et al (2022) Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis. Drug Discov Today. https://doi.org/10.1016/j.drudis.2021.12.012
Bates J et al (2020) Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol. https://doi.org/10.1016/j.jhep.2020.04.037
Benyon RC, Arthur MJ (2001) Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis. https://doi.org/10.1055/s-2001-17552
Brenner C, Galluzzi L, Kepp O, Kroemer G (2013) Decoding cell death signals in liver inflammation. J Hepatol. https://doi.org/10.1016/j.jhep.2013.03.033
Capelletti MM, Manceau H, Puy H, Peoc’h K (2020) Ferroptosis in Liver Diseases: An Overview. Int J Mol Sci. https://doi.org/10.3390/ijms21144908
Chen YL et al (2011) Sorafenib inhibits transforming growth factor beta1-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes. Hepatology. https://doi.org/10.1002/hep.24254
Corbit KC et al (2003) Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J Biol Chem. https://doi.org/10.1074/jbc.M210015200
Deng YR et al (2013) STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib. J Autoimmun. https://doi.org/10.1016/j.jaut.2013.07.008
Dixon SJ et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. https://doi.org/10.1016/j.cell.2012.03.042
Dixon SJ et al (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. https://doi.org/10.7554/eLife.02523
Eberhardt J, Santos-Martins D, Tillack AF, Forli S (2021) AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model. https://doi.org/10.1021/acs.jcim.1c00203
Friedmann Angeli JP et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. https://doi.org/10.1038/ncb3064
Gandhi CR (2017) Hepatic stellate cell activation and pro-fibrogenic signals. J Hepatol. https://doi.org/10.1016/j.jhep.2017.06.0010
Gao M, Monian P, Quadri N, Ramasamy R, Jiang X (2015) Glutaminolysis and Transferrin Regulate Ferroptosis. Mol Cell. https://doi.org/10.1016/j.molcel.2015.06.011
Gao J et al (2020) Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis. J Hepatol. https://doi.org/10.1016/j.jhep.2020.04.044
Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. https://doi.org/10.1038/s41580-020-00324-8
Jophlin LL, Cao S, Shah VH (2020) The Transcriptome of Hepatic Fibrosis Revealed by Single-Cell RNA Sequencing. Hepatology. https://doi.org/10.1002/hep.31155
Karvar S et al (2020) Moesin, an Ezrin/Radixin/Moesin Family Member Regulates Hepatic Fibrosis. Hepatology. https://doi.org/10.1002/hep.31078
Kaseb AO et al (2021) A Prospective Phase II Study of Safety and Efficacy of Sorafenib Followed by (90)Y Glass Microspheres for Patients with Advanced or Metastatic Hepatocellular Carcinoma. J Hepatocell Carcinoma. https://doi.org/10.2147/JHC.S318865
Keller ET, Fu Z, Brennan M (2004) The role of Raf kinase inhibitor protein (RKIP) in health and disease. Biochem Pharmacol. https://doi.org/10.1016/j.bcp.2004.04.024
Kisseleva T, Brenner D (2021) Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. https://doi.org/10.1038/s41575-020-00372-7
Kong Z, Liu R, Cheng Y (2019) Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2018.11.030
Li ZJ et al (2021) Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin. https://doi.org/10.1038/s41401-020-0478-3
Louandre C et al (2013) Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer. https://doi.org/10.1002/ijc.28159
Marcos LA et al (2011) Mechanisms of liver fibrosis associated with experimental Fasciola hepatica infection: roles of Fas2 proteinase and hepatic stellate cell activation. J Parasitol. https://doi.org/10.1645/GE-2420.1
Stockwell BR (2022) Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. https://doi.org/10.1016/j.cell.2022.06.003
Stockwell BR et al (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. https://doi.org/10.1016/j.cell.2017.09.021
Sun X et al (2016) Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. https://doi.org/10.1002/hep.28251
Trakul N, Rosner MR (2005) Modulation of the MAP kinase signaling cascade by Raf kinase inhibitory protein. Cell Res. https://doi.org/10.1038/sj.cr.7290258
Tsuchida T, Friedman SL (2017) Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. https://doi.org/10.1038/nrgastro.2017.38
Wenzel SE et al (2017) PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell. https://doi.org/10.1016/j.cell.2017.09.044
Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. https://doi.org/10.1093/nar/gkm290
Wilhelm S et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. https://doi.org/10.1038/nrd2130
Xie Y et al (2016) Ferroptosis: process and function. Cell Death Differ. https://doi.org/10.1038/cdd.2015.158
Yang WS, Stockwell BR (2016) Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2015.10.014
Yeung K et al (1999) Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature. https://doi.org/10.1038/43686
Yeung K et al (2000) Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol. https://doi.org/10.1128/MCB.20.9.3079-3085.2000
Yoshiji H et al (2002) Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology. https://doi.org/10.1053/jhep.2002.35625
Yuan S et al (2022) Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF-1alpha/SLC7A11 pathway. Cell Prolif. https://doi.org/10.1111/cpr.13158
Zhang Z et al (2018) Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells. Autophagy. https://doi.org/10.1080/15548627.2018.1503146
Zhang ZL et al (2021) Dihydroartemisinin alleviates hepatic fibrosis through inducing ferroptosis in hepatic stellate cells. BioFactors. https://doi.org/10.1002/biof.1764
Zheng J et al (2021) Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. https://doi.org/10.1038/s41419-021-03998-w
Funding
This study was supported by Humanities and Social Sciences Research Project of the Ministry of Education in 2020 (20YJC890054), Fujian Provincial Young Teachers' Education Research Project (Science and Technology category) (JAT220329).
Author information
Authors and Affiliations
Contributions
Conceptualization, Z.P.X., C.H.H.; methodology, Z.P.X, Y.Z. and C.H.H; software, Y.Z. and M.L; writing—original draft preparation, Z.P.X., M.L and C.H.H.; writing—review and editing, Z.P.X., M.L and C.H.H.; funding acquisition, M.L., Z.P.X.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Handling editor: S. Broer.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Xie, Z., Zhou, Y., Lin, M. et al. Binding of berberine to PEBP1 synergizes with sorafenib to induce the ferroptosis of hepatic stellate cells. Amino Acids 55, 1867–1878 (2023). https://doi.org/10.1007/s00726-023-03345-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-023-03345-7