Progesterone Acts Synergistically with Niraparib in Ovarian Cancer by Promoting Ferroptosis via the PR/SCD1/ Fatty Acid Oxidation Pathway

Abstract

PARP inhibitors (PARPi) play an increasing role in the treatment of ovarian cancer (OC). However, more than 40% BRCA1/2-deficient patients do not respond to PARPi, and wild-type BRCA cases have no significant benefit. Here, we demonstrated progesterone acted synergistically with niraparib in ovarian cancer cells with or without BRCA deficient. This synergism has been confirmed in the ovarian cancer organoid model and in vivo experiments. Furthermore, progesterone can enhance activity of niraparib in ovarian cancer via ferroptosis induction by upregulating progesterone receptor (PR)/SCD1-mediated fatty acid metabolism and enhancing mitochondrial damage. In clinical cases, PR and SCD1 were expressed at higher levels in PARPi sensitive cases compared with resistant cases, and high PR expression was associated with improved prognosis and higher sensitivity to PARPi in OC. This study provides new strategies for improving the efficacy of PARPi in ovarian cancer.