Double-stranded RNA adenosine deaminases suppress ferroptosis through regulating SCD1

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Death Mechanisms

Background:

• Double-stranded RNA adenosine deaminases 1 and 2 (ADAR1/2) catalyze A-to-I RNA editing, a process linked to cancer progression and drug resistance.
• While ADAR1/2's role in apoptosis is known, their involvement in ferroptosis remains unexplored.

Purpose of the Study:

• To investigate the role of ADAR1/2 in ferroptosis regulation in cancer.
• To determine the relationship between ADAR1/2, Stearoyl-CoA desaturase 1 (SCD1), and ferroptosis.

Main Methods:

• Analysis of ADAR1/2 and SCD1 expression in cervical, breast, and colon cancers.
• Depletion of ADAR1/2 in cancer cells and assessment of ferroptosis markers (lipid droplets) and SCD1 levels.
• Overexpression of wild-type ADAR1 (WT) and RNA editing-inactive mutant (EAA) to evaluate ferroptosis sensitivity and SCD1 expression.
• Assessment of ferroptosis sensitivity upon combined ADAR1/2 and SCD1 depletion.

Main Results:

• ADAR1/2 were upregulated in cervical, breast, and colon cancers but did not affect drug-induced apoptosis.
• ADAR1/2 depletion increased lipid droplets and downregulated SCD1, sensitizing cells to ferroptosis.
• ADAR1/2 and SCD1 expression positively correlated in cancers with elevated ADAR1/2.
• Overexpression of WT ADAR1 conferred ferroptosis resistance via SCD1, while EAA mutant cells were sensitive.
• SCD1 depletion sensitized WT ADAR1 cells to ferroptosis.

Conclusions:

• ADAR1/2 suppress ferroptotic cell death through RNA editing activity, specifically by regulating SCD1.
• ADAR1/2 play a novel role in suppressing ferroptosis.
• Targeting ADAR1/2 presents a potential strategy to enhance chemotherapeutic efficacy in cancers with high RNA editing activity.