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, PPARa, 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, PPARa, GPX4, SCD1, and ACSL3) to reduce lipid peroxidation. Hence, modulating FXR activity may be beneficial to overcome ferroptosis-mediated degenerative diseases.
Development of functional neurons is a complex orchestration of several signaling pathways controlling cell proliferation, differentiation, and homeostasis. However, details about the involved factors are not fully understood. The balance of antioxidants and vitamins is important for neuronal survival, synaptic plasticity, and early neuronal development; thus, we hypothesized that ferroptosis — a lipid peroxidation dependent cell death modality that is inhibited by antioxidanats — needs to be suppressed to gain neurons. Our study shows that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids. Intriguingly, impaired neuronal development in conditions lacking antioxidants can be fully restored when ferroptosis is specifically inhibited by ferrostatin-1, or neuronal differentiation occurs in the presence of sufficient amounts of vitamin A. Mechanistically, vitamin A activates the heterodimeric nuclear receptor complex Retinoic Acid Receptor (RAR)/Retinoid X Receptor (RXR), which upregulates expression of the ferroptosis regulators GPX4, FSP1, GCH1, and ACSL3, amongst others. Therefore, our study reveals that above a certain threshold, vitamin A increases expression of essential cellular gatekeepers of lipid peroxidation. This study uncovers a critical process during early neuronal development, where suppression of ferroptosis by radical-trapping antioxidants or vitamin A is required to obtain maturing neurons and proper laminar organization in cortical organoids.
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