Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis

Juliane Tschuck, Lea Theilacker, Ina Rothenaigner, Stefanie A. I. Weiß, Banu Akdogan, Lam Van Thanh, Constanze Müller, Roman Graf, Stefanie Brandner, Christian Pütz, Tamara Rieder, Philippe Schmitt-Kopplin, Michelle Vincendeau, Hans Zischka, Kenji Schorpp and Kamyar Hadian ()
Additional contact information
Juliane Tschuck: Research Unit Signaling and Translation, Helmholtz Zentrum München
Lea Theilacker: Research Unit Signaling and Translation, Helmholtz Zentrum München
Ina Rothenaigner: Research Unit Signaling and Translation, Helmholtz Zentrum München
Stefanie A. I. Weiß: Research Unit Signaling and Translation, Helmholtz Zentrum München
Banu Akdogan: Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München
Lam Van Thanh: Institute of Virology, Helmholtz Zentrum München
Constanze Müller: Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München
Roman Graf: Research Unit Signaling and Translation, Helmholtz Zentrum München
Stefanie Brandner: Research Unit Signaling and Translation, Helmholtz Zentrum München
Christian Pütz: Research Unit Signaling and Translation, Helmholtz Zentrum München
Tamara Rieder: Technical University Munich, School of Medicine
Philippe Schmitt-Kopplin: Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München
Michelle Vincendeau: Institute of Virology, Helmholtz Zentrum München
Hans Zischka: Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München
Kenji Schorpp: Research Unit Signaling and Translation, Helmholtz Zentrum München
Kamyar Hadian: Research Unit Signaling and Translation, Helmholtz Zentrum München

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Ferroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. Recent research has identified many regulators that induce or inhibit ferroptosis; yet, many regulatory processes and networks remain to be elucidated. In this study, we performed a chemical genetics screen using small molecules with known mode of action and identified two agonists of the nuclear receptor Farnesoid X Receptor (FXR) that suppress ferroptosis, but not apoptosis or necroptosis. We demonstrate that in liver cells with high FXR levels, knockout or inhibition of FXR sensitized cells to ferroptotic cell death, whereas activation of FXR by bile acids inhibited ferroptosis. Furthermore, FXR inhibited ferroptosis in ex vivo mouse hepatocytes and human hepatocytes differentiated from induced pluripotent stem cells. Activation of FXR significantly reduced lipid peroxidation by upregulating the ferroptosis gatekeepers GPX4, FSP1, PPARα, SCD1, and ACSL3. Together, we report that FXR coordinates the expression of ferroptosis-inhibitory regulators to reduce lipid peroxidation, thereby acting as a guardian of ferroptosis.

Date: 2023
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DOI: 10.1038/s41467-023-42702-8

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