Nanoparticle Targeting in Chemo‐Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance

Abstract Platinum (Pt)‐based chemotherapy is the main treatment for ovarian cancer (OC); however, most patients develop Pt resistance (Pt‐R). This work shows that Pt‐R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B‐1 (SR‐B1). SR‐B1 blockade using synthetic cholesterol‐poor HDL‐like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and inhibition of tumor growth. Reduced cholesterol accumulation in cancer cells induces lipid oxidative stress through the reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion induces decreased cholesterol uptake through SR‐B1 and re‐sensitizes OC cells to Pt. Mechanistically, GPx4 knockdown causes lower expression of the histone acetyltransferase EP300, leading to reduced deposition of histone H3 lysine 27 acetylation (H3K27Ac) on the sterol regulatory element binding transcription factor 2 (SREBF2) promoter and suppressing expression of this key transcription factor involved in the regulation of cholesterol metabolism. SREBF2 downregulation leads to decreased SR‐B1 expression and diminished cholesterol uptake. Thus, chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR‐B1 expression through SREBF2. Targeting SR‐B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt‐R OC.