| Liu Xiaoxiao,Wang Yuchen,Geng Shangyi,et al.Mechanism of leptin in mediating radioresistance in triple-negative breast cancer through the inhibition of ferroptosis pathway[J].Chinese Journal of Radiological Medicine and Protection,2026,46(1):20-28 |
| Mechanism of leptin in mediating radioresistance in triple-negative breast cancer through the inhibition of ferroptosis pathway |
| Received:June 20, 2025 |
| DOI：10.3760/cma.j.cn112271-20250620-00207 |
| KeyWords:Triple-negative breast cancer Leptin Ferroptosis Lipocalin 2 Radioresistance |
| FundProject:国家自然科学基金(82172839,82374229,82573452,82574765);陕西省青年科技新星项目(2024ZC-KJXX-083) |
| Author Name | Affiliation | E-mail | | Liu Xiaoxiao | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Wang Yuchen | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Geng Shangyi | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Dang Yongze | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Li Xia | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Guo Wei | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Ke Yue | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Pan Shupei | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Qu Jingkun | Second Affiliated Hospital of Xi'an Jiaotong University, Breast Disease Diagnosis and Treatment Center, Xi'an 710004, China | xixizhao@xjtu.edu.cn | | Ma Hongbing | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | | | Zhao Xixi | Second Affiliated Hospital of Xi'an Jiaotong University, Department of Radiation Oncology, Xi'an 710004, China | |
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| Abstract:: |
| Objective To investigate the effect of leptin on radiotherapy resistance in triple-negative breast cancer by regulating ferroptosis-related signaling pathways. Methods Different concentrations of leptin (0, 50, 100, 200 ng/ml) were used to treat MDA-MB-231 cells, and the treatment conditions were optimized through western blot analysis and cell proliferation and toxicity assays. MDA-MB-231 cells were divided into four groups: control group, leptin group (200 ng/ml, 48 h), irradiation group (4 Gy X-rays), and irradiation + leptin group. Malondialdehyde (MDA) levels were detected using a microplate reader, and reactive oxygen species (ROS) and cell apoptosis levels were measured using flow cytometry. Western blotting was used to detect the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). Key molecules were screened using bioinformatics (GEO and FerrDb databases) and the expression of lipid carrier protein 2 (LCN2) was validated. siRNA was used to knock down LCN2, and its effect on leptin-regulated SLC7A11/GPX4 expression was evaluated. Immunohistochemistry was performed on breast cancer tissues. Results Compared to the 0 ng/ml, 48 h group, leptin (200 ng/ml, 48 h) significantly increased the expression level of p-STAT3 and cell proliferation in MDA-MB-231 cells (t = 32.85, 17.25, P < 0.05). Compared to the control group, leptin significantly reduced the apoptosis rate of MDA-MB-231 cells (t = -6.87, P < 0.05), and markedly attenuated irradiation-induced apoptosis (t = -9.46, P < 0.05). Compared to the irradiation group, leptin inhibited the MDA and ROS levels induced by radiation in MDA-MB-231 cells (t = -4.67, -14.82, P < 0.05), and simultaneously upregulated the expression of ferroptosis-suppressing proteins SLC7A11 and GPX4 (t = 7.11, 8.36, P < 0.05), partially reversing radiation-induced ferroptosis. Mechanistic studies showed that under irradiation conditions, leptin significantly upregulated the expression of LCN2 in MDA-MB-231 cells (t = 8.96, P < 0.05). After LCN2 was knocked down by siRNA, the upregulation effects of SLC7A11 and GPX4 were reversed (t = -5.85, -15.58, P < 0.05), suggesting that leptin maintains the stability of SLC7A11/GPX4 through LCN2, thereby inhibiting ferroptosis and enhancing radiotherapy resistance. Immunohistochemical analysis further showed that in breast cancer tissues with high leptin expression, the levels of LCN2, SLC7A11, and GPX4 were significantly elevated (t = 50.57, 10.14, 13.81, P < 0.05). 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. |
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