AhR signaling modulates Ferroptosis by regulating SLC7A11 expression

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The aryl hydrocarbon receptor (AhR) is a transcription factor involved in development and immune responses.
• AhR's role in oxidative stress is known, but its connection to ferroptosis is unclear.
• Ferroptosis is a regulated cell death pathway dependent on iron and lipid peroxidation.

Purpose of the Study:

• To investigate the role of AhR in ferroptosis.
• To elucidate the molecular mechanisms linking AhR to ferroptosis.
• To determine if AhR ligands can modulate ferroptosis.

Main Methods:

• Pharmacological inhibition and genetic ablation of AhR.
• Erastin-induced ferroptosis assays.
• Measurement of SLC7A11 expression and lipid peroxidation.
• Analysis of post-translational modifications of SLC7A11.
• Treatment with indole 3-pyruvate (I3P), an AhR ligand.

Main Results:

• AhR inactivation or deletion enhanced erastin-induced ferroptosis.
• This enhancement was linked to suppressed SLC7A11 expression and increased lipid peroxidation.
• Evidence for post-translational modifications of SLC7A11 during ferroptosis was observed.
• The AhR ligand I3P protected cells from ferroptosis via an AhR-dependent pathway.

Conclusions:

• AhR transcriptionally regulates SLC7A11, a key mediator of ferroptosis.
• AhR activation suppresses ferroptosis by maintaining SLC7A11 expression and preventing lipid peroxidation.
• AhR is a critical suppressor of ferroptosis, promoting cell survival under oxidative stress.