2. Academic Validation
  3. Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis

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

  • Nat Commun. 2023 Oct 30;14(1):6908. doi: 10.1038/s41467-023-42702-8.
Juliane Tschuck 1,  Lea Theilacker 1,  Ina Rothenaigner 1,  Stefanie A I Weiß 1,  Banu Akdogan 2,  Van Thanh Lam 3,  Constanze Müller 4,  Roman Graf 1,  Stefanie Brandner 1,  Christian Pütz 1,  Tamara Rieder 5,  Philippe Schmitt-Kopplin 4,  Michelle Vincendeau 3,  Hans Zischka 2 5,  Kenji Schorpp 1,  Kamyar Hadian 6
Affiliations

Affiliations

  • 1 Research Unit Signaling and Translation, Helmholtz Zentrum München, Neuherberg, Germany.
  • 2 Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 3 Institute of Virology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 4 Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Neuherberg, Germany.
  • 5 Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, Munich, Germany.
  • 6 Research Unit Signaling and Translation, Helmholtz Zentrum München, Neuherberg, Germany. [email protected].
PMID: 37903763 DOI: 10.1038/s41467-023-42702-8
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.

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