Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Medicine

Background:

• Ferroptosis is a regulated cell death pathway dependent on iron and lipid peroxidation.
• While regulators of ferroptosis are known, its complex regulatory networks require further elucidation.

Purpose of the Study:

• To identify novel regulators of ferroptosis using a chemical genetics approach.
• To investigate the role of the nuclear receptor Farnesoid X Receptor (FXR) in ferroptosis regulation.

Main Methods:

• Chemical genetics screen using small molecules with known mechanisms of action.
• In vitro studies using liver cells, including knockout and inhibition models.
• Ex vivo experiments with mouse and human hepatocytes.

Main Results:

• Two agonists of Farnesoid X Receptor (FXR) were identified as suppressors of ferroptosis.
• FXR knockout or inhibition sensitized liver cells to ferroptosis, while FXR activation by bile acids inhibited it.
• FXR activation reduced lipid peroxidation by upregulating key ferroptosis gatekeepers: GPX4, FSP1, PPARα, SCD1, and ACSL3.

Conclusions:

• FXR acts as a key regulator that suppresses ferroptosis.
• FXR coordinates the expression of ferroptosis-inhibitory genes, thereby reducing lipid peroxidation and protecting cells.
• FXR functions as a guardian against ferroptotic cell death.