Farnesoid X Receptor suppresses lipid peroxidation and ferroptosis

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