Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis
Ovarian cancer (OC) is prone to peritoneum or omentum dissemination, thus giving rise to the formidable challenge of unresectable surgery and a dismal survival rate. Although niraparib holds a pivotal role in the maintenance treatment of OC, its effect on suppressing metastases during primary interv...
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Elsevier
2025-03-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000412 |
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| author | Ning Jin Yi-yu Qian Xiao-fei Jiao Zhen Wang Xin Li Wen Pan Jin-kai Jiang Pu Huang Si-yuan Wang Ping Jin Qing-lei Gao Dan Liu Yu Xia |
| author_facet | Ning Jin Yi-yu Qian Xiao-fei Jiao Zhen Wang Xin Li Wen Pan Jin-kai Jiang Pu Huang Si-yuan Wang Ping Jin Qing-lei Gao Dan Liu Yu Xia |
| author_sort | Ning Jin |
| collection | DOAJ |
| description | Ovarian cancer (OC) is prone to peritoneum or omentum dissemination, thus giving rise to the formidable challenge of unresectable surgery and a dismal survival rate. Although niraparib holds a pivotal role in the maintenance treatment of OC, its effect on suppressing metastases during primary intervention remains enigmatic. Recently, we initiated a prospective clinical study (NCT04507841) in order to evaluate the therapeutic efficacy of neoadjuvant niraparib monotherapy for advanced OC with homologous recombination deficiency. An analysis of patient tumor burden before and after the niraparib challenge showed a remarkable vulnerability of OC intraperitoneal metastases to niraparib exposure. This killing capacity of niraparib was closely associated with the accumulation of fatty acids within the abdomen, which was confirmed by the increased susceptibility of tumor cells to niraparib treatment in the presence of fatty acids. In the context of abundant fatty acids, niraparib elevated intracellular levels of fatty acids and lipid peroxidation, leading to subsequent tumor cell ferroptosis in a p53 and BRCA-independent manner. Notably, under niraparib exposure, a critical fatty acid transporter CD36 was dramatically upregulated in tumors, facilitating excessive uptake of fatty acids. Pharmacological inhibition of either ferroptosis or CD36 impaired the anti-tumor activity of niraparib both in vitro and in murine intraperitoneal ID8 tumor models. Our findings demonstrate ferroptosis as a novel mechanism underlying the regression of OC metastases induced by niraparib, thereby offering tantalizing prospects for the frontline application of this agent in the management of OC. |
| format | Article |
| id | doaj-art-5a729aed63b94bec91b64e476cbf0b2b |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-5a729aed63b94bec91b64e476cbf0b2b2025-02-08T05:00:23ZengElsevierRedox Biology2213-23172025-03-0180103528Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosisNing Jin0Yi-yu Qian1Xiao-fei Jiao2Zhen Wang3Xin Li4Wen Pan5Jin-kai Jiang6Pu Huang7Si-yuan Wang8Ping Jin9Qing-lei Gao10Dan Liu11Yu Xia12Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, ChinaCancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, ChinaCancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, ChinaDepartment of Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China; Clinical Medicine Research Centre of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, ChinaCancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, ChinaCancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, ChinaCancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, ChinaDepartment of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaDepartment of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, ChinaCancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, ChinaCancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China; Corresponding author. Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China; Corresponding author. Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China; Department of Gynecology and Obstetrics, Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China; Corresponding author. Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital Tongji Medical College Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.Xiayu_hb@tjh.tjmu.edu.cnOvarian cancer (OC) is prone to peritoneum or omentum dissemination, thus giving rise to the formidable challenge of unresectable surgery and a dismal survival rate. Although niraparib holds a pivotal role in the maintenance treatment of OC, its effect on suppressing metastases during primary intervention remains enigmatic. Recently, we initiated a prospective clinical study (NCT04507841) in order to evaluate the therapeutic efficacy of neoadjuvant niraparib monotherapy for advanced OC with homologous recombination deficiency. An analysis of patient tumor burden before and after the niraparib challenge showed a remarkable vulnerability of OC intraperitoneal metastases to niraparib exposure. This killing capacity of niraparib was closely associated with the accumulation of fatty acids within the abdomen, which was confirmed by the increased susceptibility of tumor cells to niraparib treatment in the presence of fatty acids. In the context of abundant fatty acids, niraparib elevated intracellular levels of fatty acids and lipid peroxidation, leading to subsequent tumor cell ferroptosis in a p53 and BRCA-independent manner. Notably, under niraparib exposure, a critical fatty acid transporter CD36 was dramatically upregulated in tumors, facilitating excessive uptake of fatty acids. Pharmacological inhibition of either ferroptosis or CD36 impaired the anti-tumor activity of niraparib both in vitro and in murine intraperitoneal ID8 tumor models. Our findings demonstrate ferroptosis as a novel mechanism underlying the regression of OC metastases induced by niraparib, thereby offering tantalizing prospects for the frontline application of this agent in the management of OC.http://www.sciencedirect.com/science/article/pii/S2213231725000412Ovarian cancerNiraparibIntraperitoneal metastasesFerroptosisFatty acidCD36 |
| spellingShingle | Ning Jin Yi-yu Qian Xiao-fei Jiao Zhen Wang Xin Li Wen Pan Jin-kai Jiang Pu Huang Si-yuan Wang Ping Jin Qing-lei Gao Dan Liu Yu Xia Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis Redox Biology Ovarian cancer Niraparib Intraperitoneal metastases Ferroptosis Fatty acid CD36 |
| title | Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis |
| title_full | Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis |
| title_fullStr | Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis |
| title_full_unstemmed | Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis |
| title_short | Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis |
| title_sort | niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting cd36 dependent ferroptosis |
| topic | Ovarian cancer Niraparib Intraperitoneal metastases Ferroptosis Fatty acid CD36 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000412 |
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