ADAR1 Regulates Lipid Remodeling to Dictate Ferroptosis Sensitivity

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies.
• Adenosine deaminase acting on RNA 1 (ADAR1) is implicated in TNBC development.
• ADAR1 may protect TNBC from metabolic stress.

Purpose of the Study:

• To investigate the role of ADAR1 in ferroptosis, an iron-dependent cell death pathway, in TNBC.
• To identify therapeutic strategies targeting ADAR1-mediated metabolic vulnerabilities in TNBC.

Main Methods:

• ADAR1 knockdown in TNBC cells.
• Sensitivity assays with GPX4 inhibitors.
• Liquid chromatography-mass spectrometry (LC-MS) for lipid profiling.
• Transcriptomic analysis.
• Phenotypic drug screening with a ferroptosis-focused library.

Main Results:

• ADAR1 knockdown sensitized TNBC cells to GPX4 inhibitors, indicating a role in ferroptosis regulation.
• Loss of ADAR1 increased polyunsaturated fatty acid phospholipids (PUFA-PL), key drivers of ferroptosis.
• Transcriptomic analysis identified the proto-oncogene MDM2 as involved in lipid remodeling upon ADAR1 loss.
• Cobimetinib was identified as a potential drug-repurposing candidate to synergize with ADAR1 loss.

Conclusions:

• ADAR1 acts as a homeostatic factor protecting TNBC from ferroptosis.
• Targeting ADAR1 could exploit a metabolic vulnerability in TNBC.
• Findings support further investigation for novel TNBC therapeutic strategies.