Mechanism of Leptin Inhibiting Ferroptosis-Mediated Radioresistance in Triple-Negative Breast Cancer via the LCN2/SLC7A11/GPX4 Pathway

Objective:To investigate the role of leptin in regulating ferroptosis-related signaling pathways and its impact on radioresistance in triple-negative breast cancer.Methods: The treatment conditions of leptin were optimized using Western blot analysis and Cell counting kit-8 (CCK-8) assay. Triple-negative breast cancer cell lines MDA-MB-231 and BT-549 were divided into control, leptin, ionizing radiation, and ionizing radiation plus leptin groups. Malondialdehyde (MDA) levels were measured using a microplate reader, while reactive oxygen species (ROS) accumulation and apoptosis were assessed by flow cytometry. Western blot analysis was performed to detect phosphorylated signal transducer and activator of transcription 3 (p-STAT3), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). In addition, bioinformatics analysis was applied to screen potential regulatory molecules, and lipocalin 2 (LCN2) expression was validated. The role of LCN2 in leptin-mediated regulation of SLC7A11/GPX4 was further evaluated by siRNA-mediated knockdown, and immunohistochemistry was conducted in breast cancer tissues. Results: Leptin promoted the proliferation of triple-negative breast cancer cells, inhibited apoptosis, reduced MDA and ROS levels, and upregulated SLC7A11 and GPX4, thereby attenuating radiation-induced ferroptosis. Silencing of LCN2 diminished the leptin-induced upregulation of SLC7A11/GPX4, suggesting that LCN2 was a key mediator of leptin-driven ferroptosis suppression. Immunohistochemistry further revealed that breast cancer tissues with high leptin expression exhibited significantly elevated levels of LCN2, SLC7A11, and GPX4.Conclusion: Leptin inhibits ferroptosis through the LCN2/SLC7A11/GPX4 signaling pathway, contributing to radioresistance in triple-negative breast cancer, and may serve as a potential target for ferroptosis-based radiosensitization strategies.