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Tschuck, J. ; Theilacker, L. ; Rothenaigner, I. ; Weiß, S.A.I. ; Akdogan, B. ; Lam, T.V. ; Müller, C. ; Graf, R. ; Brandner, S. ; Pütz, C. ; Rieder, T.* ; Schmitt-Kopplin, P. ; Vincendeau, M. ; Zischka, H. ; Schorpp, K. ; Hadian, K.

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

Nat. Commun. 14:6908 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Nuclear Receptor; Fxr; Mechanisms; Ligands
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 14, Issue: 1, Pages: , Article Number: 6908 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Signaling and Translation (SAT)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Virology (VIRO)
Research Unit Analytical BioGeoChemistry (BGC)
Grants Projekt DEAL