Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors

Sep 21, 2026

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BRCA1 is frequently mutated in ovarian and breast cancers, and its loss causes homologous recombination repair deficiency, leading to genomic instability and PARP inhibitor (PARPi) synthetic lethality. Beyond genome safeguards, BRCA1’s tumor-suppressive roles are poorly defined. This study shows BRCA1 promotes ferroptosis by catalyzing K6-linked polyubiquitination of GPX4 and accelerating GPX4 degradation. GPX4 depletion suppresses BRCA1-deficient ovarian cancer xenografts, while PARPi triggers ferroptosis and GPX4 inhibition markedly enhances PARPi-induced ferroptosis. Combined GPX4 inhibition and PARPi yields synergistic antitumor effects in BRCA1-deficient models.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

BRCA1 loss and cancer vulnerability

PARP inhibitors and synthetic lethality

Mechanistic findings on BRCA1–GPX4–ferroptosis

Redox Biology 76 (2024) 103350 Contents lists available at ScienceDirect Redox Biology journal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox) | Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors
Xuexia Xiea,b,1, Congcong Chen b,1, Cong Wang a,1, Yongjian Guo a, Binghe Suna, Jiaxin Tiana, Jin Yana, Dake Li c, Guo Chena,*
a School of Biopharmacy, China Pharmaceutical University, Nanjing, 211198, China
b Department of Anesthesiology and General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, China
c Department of Gynecology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004, China | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords: BRCA1
Ferroptosis
PARP inhibitors GPX4 ubiquitination Ovarian cancer | | BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic antitumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers. | 1. Introduction As one of the most common mutated genes, loss of function of BRCA1 plays critical roles in tumorigenesis and cancer progression in various cancers, especially in ovarian and breast cancers [1]. Approximately 20–30 % of ovarian or breast cancer patients carry BRCA1 mutations, which are associated with poor overall survival [2]. BRCA1 gene is located on chromosome 17, consists of 22 exons and encodes a protein of 1863 amino acids [3]. BRCA1 protein is the main controller in DNA double-strand break (DSB) repair pathway choice between homologous recombination (HR) and non-homologous end-joining (NHEJ) repair, it accumulates at DNA DSB sites and favors HR repair during S/G2 phase [4–6]. Meanwhile, BRCA1 is also involved in DNA replication fork protection during DNA replication stress [7]. Thus, loss of BRCA1 leads to genomic instability characterized by increased DNA breaks and chromosomal aberrations. As an important cancer susceptibility gene, mutations in BRCA1 confers lifetime risks of breast and ovarian cancer up to 80 % and 50 % respectively [2]. BRCA1-deficient cancers display an autonomous inflammatory state and are intrinsically resistant to immune checkpoint blockade (ICB) and MEK inhibitor [8–10]. Similar with BRCA1, the other breast cancer susceptibility gene, BRCA2 is also involved in regulation of DSBs repair and frequently mutated in ovarian cancer cells. However, only BRCA2 mutations, but not BRCA1 mutations, are associated with improved chemotherapy response compared with wild-type (WT) BRCA1/2 in patients with ovarian cancer [11,12]. In addi

FAQs

How does BRCA1 influence ferroptosis in BRCA1-deficient cancer cells?

BRCA1 promotes ferroptosis by catalyzing K6-linked polyubiquitination of GPX4, which accelerates GPX4 degradation. This increases ferroptosis susceptibility in cancer cells.

What is the relationship between PARP inhibitors and ferroptosis in ovarian cancer?

PARP inhibitors trigger ferroptosis in ovarian cancer cells. In BRCA1-deficient cells, inhibiting GPX4 markedly increases PARPi-induced ferroptosis.

Why does combining a GPX4 inhibitor with PARP inhibitors enhance antitumor effects?

The combination produces synergistic antitumor efficacy by strengthening ferroptosis execution in BRCA1-deficient ovarian cancer cells, patient-derived organoids, and xenografts.

Sep 21, 2026

Uploaded by Levi