Farnesoid X Receptor suppresses lipid peroxidation and ferroptosis

• DOI: 10.1101/2022.10.07.511245
• Publication Date: 2022-10-07T16:25:17Z
• Authors: Juliane Tschuck; Lea Theilacker; Ina Rothenaigner; Stefanie A. I. Weiß; Banu Akdogan; Constanze Müller; Roman Graf; Stefanie Brandner; Christian Pütz; Tamara Rieder; Philippe Schmitt-...; Hans Zischka; Kenji Schorpp; Kamyar Hadian
• Keywords: GPX4; Farnesoid X receptor

ABSTRACT Objective Ferroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. The recent decade of research has uncovered many regulators driving ferroptosis as well cellular gatekeepers preventing ferroptosis. Yet, processes and networks remain to be elucidated. Methods results In this study, we performed chemical screen using small molecules with known mode action identified two agonists (Turofexorate Fexaramine) the nuclear receptor Farnesoid X Receptor (FXR), also NR1H4, suppress ferroptosis, but not apoptosis or necroptosis. Further, demonstrate in liver cells high FXR protein levels, inhibition sensitizes undergo ferroptotic death, while activation inhibits Importantly, ex vivo primary mouse hepatocytes. Activation by Turofexorate Fexaramine significantly reduces Mechanistically, overexpression bile acids upregulates ferroptosis-inhibitory FSP1, PPARα, GPX4, SCD1, ACSL3 reduce peroxidized lipids counteract Conclusion via upregulation number proteins (FSP1, ACSL3) Hence, modulating activity may beneficial overcome ferroptosis-mediated degenerative diseases.