A New Guardian of Ferroptosis: Farnesoid X Receptor
Understanding ferroptosis is essential for addressing degenerative diseases and certain cancers. Researchers, led by Dr. Kamyar Hadian from Helmholtz Munich, revealed that the Farnesoid X Receptor (FXR), activated by bile acids, serves as a master regulator of ferroptosis, suggesting potential therapeutic avenues for disease treatment.
Cell death is very important for the proper functioning of almost all multicellular organisms. Cell death helps maintain tissue homeostasis by eliminating damaged or dysfunctional cells. There are a number of different cell death programs that occur in a regulated manner. One of them is ferroptosis, which involves iron-dependent oxidative damage to cellular lipids, which are essential components of cell membranes. This leads to the breakdown of cell membranes and finally cell death. Ferroptosis is present in a number of degenerative diseases including neurodegeneration, acute kidney and liver injury, and many others. In addition, several cancers have been shown to be susceptible to ferroptotic cell death. Therefore, understanding the molecular mechanisms that regulate ferroptosis is essential to identify specific targets for therapeutic intervention. The last decade of ferroptosis research has uncovered several mechanisms that induce or inhibit ferroptosis. Yet, many regulatory details remain to be discovered.
Farnesoid X Receptor Activation by Bile Acids Prevents Ferroptotic Cell Death
A team of researchers led by Dr. Kamyar Hadian from the Research Unit Signaling and Translation at Helmholtz Munich performed a chemical genetics screen to identify novel regulators of ferroptosis. This means, that the scientists exposed cells to thousands of diverse compounds with known mode of action and subsequently assessed cell viability. This approach was employed to elucidate the pathways and regulators associated with ferroptosis. They discovered that the nuclear receptor Farnesoid X Receptor (FXR) is a potent inhibitor of lipid peroxidation and ferroptosis. The FXR is mainly expressed in the liver, kidney, and small intestine, and is activated by bile acids. This study, published in Nature Communications, demonstrates that the FXR is a master regulator of ferroptosis by upregulating the transcription of essential ferroptosis gatekeepers, thereby inhibiting lipid peroxidation and ferroptosis. Hence, the activation of FXR by bile acids or specific small molecules effectively rescued cells from ferroptotic cell death.
These findings suggest that organs and tissues that are generally at higher exposure to toxins or drug metabolites have upregulated FXR as a protective measure against ferroptotic cell death. Specific compounds that activate FXR will be evaluated in future studies as novel molecules in the treatment of degenerative diseases such asacute kidney or liver injury to prevent cell death by ferroptosis. Moreover, this study provides an unexpected novel function for bile acids as suppressors of lipid peroxidation and ferroptosis.
Tschuck et. al (2023): Farnesoid X Receptor activation by bile acids suppresses lipid peroxidation and ferroptosis. Nature Communications. DOI: https://doi.org/10.1038/s41467-023-42702-8
About the scientists
Juliane Tschuck, doctoral researcher at the Research Unit Signaling and Translation at Helmholtz Munich
Dr. Kamyar Hadian, Deputy Director of the Research Unit Signaling and Translation at Helmholtz Munich