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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Nuclear Receptor; Fxr; Mechanisms; Ligands
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 14, Heft: 1, Seiten: , Artikelnummer: 6908 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Virology (VIRO)
Research Unit Analytical BioGeoChemistry (BGC)
Förderungen Projekt DEAL