Ferroportin deficiency drives olaparib resistance in ovarian cancer via the cGAS–STING–STAT3 survival axis

BACKGROUND: Ovarian cancer (OC) remains the most lethal gynaecological malignancy, and acquired resistance to PARP inhibitors such as olaparib represents a major clinical challenge. Although dysregulation of iron metabolism has been implicated in tumorigenesis, the specific role of the iron exporter SLC40A1 (ferroportin, FPN) in mediating olaparib resistance remains poorly understood. The study aimed to elucidate the clinical significance of FPN deficiency and to explore therapeutic strategies for reversing olaparib resistance. METHODS: FPN expression was evaluated in OC samples from a clinical cohort of 19 patients, stratified by olaparib responsiveness, to determine its prognostic value. Functional mechanisms were investigated using multiple OC cell lines, patient-derived organoids (PDOs), and mouse xenograft models. We integrated analyses of iron homeostasis, ROS dynamics, DNA repair capacity, and innate immune signaling, with a focus on the cGAS-STING-STAT3 signaling cascade. The therapeutic potential of combining olaparib with the ferroptosis inducer erastin or the STING inhibitor C-176 was assessed as a strategy to overcome FPN deficiency-driven resistance. RESULTS: Clinically, FPN expression was significantly downregulated in olaparib-resistant tissues compared with sensitive controls (p < 0.05), and low FPN levels were strongly associated with poor therapeutic outcomes. Mechanistically, FPN deficiency promoted intracellular iron accumulation and ROS generation, which led to increased ferroptosis vulnerability, impaired homologous recombination repair (HRR) and concomitant activation of the cGAS-STING-STAT3 inflammatory axis, thereby driving olaparib resistance. Notably, in vivo studies demonstrated that combining olaparib with either erastin or C-176 significantly suppressed tumour growth and restored drug sensitivity compared with monotherapy (p < 0.01), supporting the translational potential of targeting this axis. CONCLUSIONS: Our study establishes a clinically relevant mechanistic connection between ferroportin deficiency and cGAS-STING-STAT3-mediated olaparib resistance in OC. We identify the FPN-ROS-cGAS-STING-STAT3 axis as an actionable vulnerability in resistant OC, indicating that this pathway is a promising therapeutic target to overcome olaparib resistance. HIGHLIGHTS: FPN loss drives olaparib resistance and predicts poor outcomes in ovarian cancer. FPN loss causes iron and ROS accumulation, impairing HRR and activating the cGAS-STING-STAT3 axis. The cGAS-STING-STAT3 pro-survival program drives olaparib resistance. STING inhibition restores olaparib sensitivity in resistant ovarian cancer.