Ginkgetin reverses cisplatin resistance in cervical cancer by regulating the Nrf2/HO-1 signaling pathway to induce ferroptosis

This study investigates whether Ginkgetin(GK) reverses cisplatin(DDP) resistance in cervical cancer cells by modulating the Nrf2/HO-1 signaling axis to induce ferroptosis, and preliminarily elucidates its underlying mechanisms. DDP-resistant cervical cancer cell line HeLa/DDP was used for in vitro experiments. Cell proliferation was assessed by CCK-8 assay; migration and invasion capabilities were evaluated via wound healing and Transwell assays; colony formation assays measured proliferative capacity. Molecular docking analyzed the binding affinity of GK to Nrf2, HO-1, and GPX4 proteins. Intracellular ROS and Fe²⁺ levels were detected using fluorescent probes. Ferroptosis-related indicators including GSH, MDA, SOD, and CAT were measured by biochemical detection. Western blot analyzed expression of key proteins. Mechanistic validation employed the Nrf2 activator sulforaphane (SFN) and ferroptosis inhibitor ferrostatin-1 (Fer-1). An in vivo subcutaneous xenograft mouse model was established to observe the reversal effect of GK on DDP-resistant tumors, combined with histopathological and immunohistochemical analyses of tissue morphology and protein expression. GK significantly inhibited the proliferation of HeLa/DDP cells and enhanced their sensitivity to DDP. Combined treatment of GK and DDP notably suppressed proliferation, migration, invasion, and colony formation abilities of HeLa/DDP cells. Molecular docking revealed strong binding affinity between GK and Nrf2. Combination treatment markedly increased ROS and Fe²⁺ levels, reduced antioxidant capacity (GSH, SOD, CAT), induced lipid peroxidation with upregulated ACSL4 expression, and downregulated Nrf2, HO-1, and GPX4 expression. Transmission electron microscopy demonstrated characteristic mitochondrial morphological changes of ferroptosis. In vivo, co-treatment significantly reduced tumor volume of DDP-resistant xenografts, enhanced DDP's antitumor efficacy, improved histopathological structures, and modulated related protein expression. GK induces ferroptosis by inhibiting the Nrf2/HO-1 signaling pathway, thereby reversing DDP resistance in cervical cancer cells. These findings provide a potential novel therapeutic strategy for clinical management of cervical cancer.