FSP1, a novel KEAP1/NRF2 target gene regulating ferroptosis and radioresistance in lung cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• KEAP1/NRF2 pathway is crucial in cellular response to stress.
• NRF2 (NFE2-like 2) is a transcription factor regulating antioxidant and detoxification genes.
• Ferroptosis is a regulated form of cell death with implications in cancer therapy.

Purpose of the Study:

• To identify key NRF2 target genes involved in ferroptosis and radioresistance in KEAP1-deficient lung cancer.
• To investigate the role of FSP1 (Ferroptosis Suppressor Protein 1) in NRF2-mediated resistance mechanisms.

Main Methods:

• Gene expression analysis in KEAP1-deficient lung cancer cell lines.
• CRISPR-Cas9 gene editing to knock out FSP1.
• Assessment of ferroptosis sensitivity using iron chelators and lipid peroxidation markers.
• Evaluation of radioresistance through clonogenic survival assays.

Main Results:

• FSP1 was identified as a novel target gene of KEAP1/NRF2.
• FSP1 expression was significantly upregulated in KEAP1-deficient lung cancer cells.
• Loss of FSP1 sensitized cells to ferroptosis induction and increased sensitivity to radiation therapy.
• FSP1 was demonstrated to be a critical mediator of NRF2-driven ferroptosis and radioresistance.

Conclusions:

• FSP1 is a key effector in the NRF2-mediated resistance to ferroptosis and radiation in KEAP1-deficient lung cancers.
• Targeting the CoQ-FSP1 axis presents a potential therapeutic strategy for these cancers.
• This study elucidates a novel mechanism of resistance in lung cancer, offering new avenues for treatment.