FOXM1 drives cisplatin resistance in ovarian cancer through STIM1-mediated SOCE and STAT1 activation

Cisplatin resistance remains a major challenge in ovarian cancer, limiting treatment efficacy and reducing patient survival. While FOXM1 and calcium (Ca²⁺ signaling have been individually implicated in chemoresistance, how transcriptional regulation is linked to Ca²⁺-dependent survival signaling remains poorly understood. To address this gap, we integrated bioinformatic analyses with functional and mechanistic studies in cisplatin-resistant (CR) ovarian cancer models. We found that FOXM1 transcriptionally activate STIM1, thereby enhancing store-operated Ca²⁺ entry (SOCE) and sustaining cytosolic Ca²⁺ levels. Elevated Ca²⁺ influx-activated downstream interferon (IFN)/STAT1 signaling and increased expression of IFN-stimulated genes associated with DNA repair and anti-apoptotic programs. FOXM1 or STIM1 depletion and pharmacological SOCE inhibition attenuated STAT1 activation and restored cisplatin sensitivity, whereas STIM1 re-expression rescued the resistance phenotype following FOXM1 depletion. Using A2780/ACR and IGROV1/ICR ovarian cancer models, together with analyses of TCGA-OV and multiple GEO cohorts, we demonstrate that FOXM1 transcriptionally activates STIM1, thereby enhancing store-operated Ca²⁺ entry and promoting STAT1-dependent IFN signaling. Genetic or pharmacological disruption of this pathway restored cisplatin sensitivity, identifying the FOXM1-STIM1/SOCE-STAT1 axis as a potential therapeutic vulnerability in platinum-resistant ovarian cancer. This study provides mechanistic insight into chemoresistance and highlights avenues for therapeutic intervention in patients with high FOXM1/STIM1 expression.