Targeting the NR3C1-ACSL4 Axis Triggers Ferroptosis to Overcome Radioresistance in Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Prostate cancer radioresistance is a significant clinical challenge.
• The glucocorticoid receptor (NR3C1) is identified as a key regulator of radioresistance.
• NR3C1's role in regulating lipid metabolism and ferroptosis in cancer is unclear.

Purpose of the Study:

• To investigate the role of the NR3C1-ACSL4 axis in prostate cancer radioresistance.
• To explore dihydroartemisinin (DHA) as a radiosensitizer targeting this pathway.
• To evaluate ACSL4 as a potential biomarker for treatment response.

Main Methods:

• Investigated NR3C1 and ACSL4 expression in prostate cancer.
• Utilized cell culture and xenograft models to study radiosensitization.
• Administered DHA and measured lipid peroxidation and ferroptosis.
• Assessed the effect of deferoxamine, a ferroptosis inhibitor.

Main Results:

• NR3C1 upregulates ACSL4, promoting proliferation, migration, and radioresistance.
• High ACSL4 expression sensitizes cells to ferroptosis.
• DHA synergizes with ACSL4 to induce ferroptosis and restore radiosensitivity in resistant cells and xenografts.
• Elevated lipid peroxidation was observed, and reversed by deferoxamine.

Conclusions:

• The NR3C1-ACSL4 axis drives prostate cancer radioresistance via lipid peroxidation.
• Targeting this axis with DHA represents a promising preclinical strategy.
• ACSL4 can serve as a predictive biomarker for this therapeutic approach.