Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) is a significant hurdle in advanced prostate cancer treatment.
• Metabolic alterations are suspected drivers of this resistance, but specific molecular mechanisms are unclear.

Purpose of the Study:

• To identify mitochondrial regulators contributing to PARPi resistance in prostate cancer.
• To explore NDUFS4 as a potential therapeutic target for overcoming PARPi resistance.

Main Methods:

• Integrated transcriptomic, functional, and clinical analyses.
• RNA sequencing and gene set enrichment analysis to identify pathway enrichment.
• Genetic knockdown and pharmacologic inhibition of NDUFS4.
• Assessment of mitochondrial function, cell viability, and ferroptosis markers.

Main Results:

• PARPi-resistant prostate cancer cells showed enriched oxidative phosphorylation (OxPhos) pathways and upregulated NDUFS4.
• Elevated NDUFS4 correlated with poorer patient survival.
• NDUFS4 depletion or inhibition resensitized resistant cells to olaparib by impairing mitochondrial respiration.
• Targeting NDUFS4 induced ferroptosis and enhanced olaparib efficacy in resistant cancer models.

Conclusions:

• NDUFS4 is a key mediator of PARPi resistance in advanced prostate cancer.
• Targeting NDUFS4 disrupts OxPhos and induces ferroptosis, presenting a therapeutic vulnerability.
• Combination strategies involving PARPi and NDUFS4 inhibition show promise for overcoming treatment resistance.