Progesterone Enhances Niraparib Efficacy in Ovarian Cancer by Promoting Palmitoleic-Acid-Mediated Ferroptosis  

作　　者：Nayiyuan Wu Xiu Zhang Chao Fang Miaochen Zhu Zhibin Wang Lian Jian Weili Tan Ying Wang He Li Xuemeng Xu Yujuan Zhou Tang-Yuan Chu Jing Wang Qianjin Liao 

机构地区：[1]The Affiliated Cancer Hospital of Xiangya School of Medicine,Central South University/Hunan Key Laboratory of Cancer Metabolism,Hunan Cancer Hospital,Changsha 410078,Hunan,China [2]Public Service Platform of Tumor Organoids Technology,Hunan Gynecological Tumor Clinical Research Center,Changsha 410013,Hunan,China [3]Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations,Changsha Medical University,Changsha 410219,Hunan,China [4]Department of Obstetrics & Gynecology,Hualien Tzu Chi Hospital,Buddhist Tzu Chi Medical Foundation,Hualien 970,Taiwan,China

出　　处：《Research》2025年第1期230-245,共16页研究(英文)

基　　金：supported by the National Natural Science Foundation of China(82003050 and 82173142);Hunan Provincial Natural Science Foundation(2023JJ30375 and 2023JJ60016);Hunan Cancer Hospital Climb Plan(2023NSFC-A004 and 2023NSFC-A003);Changsha Science and Technology Board(kh2201054);Hunan Provincial Health Commission(B2023047708).

摘　　要：Poly(adenosine 5'-diphosphate-ribose)polymerase inhibitors(PARPi)are increasingly important in the treatment of ovarian cancer.However,more than 40%of BRCA1/2-deficient patients do not respond to PARPi,and BRCA wild-type cases do not show obvious benefit.In this study,we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status.This synergy was validated in an ovarian cancer organoid model and in vivo experiments.Furthermore,we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage.In clinical cohort,it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy,and high progesterone receptor expression combined with low glutathione peroxidase 4(GPX4)expression predicted better efficacy of PARPi in patients with ovarian cancer.These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.

关 键 词：organoid model ovarian cancer niraparib ovarian cancer organoid model ferroptosis 

分 类 号：R737.31[医药卫生—肿瘤]