Abstract
Cisplatin resistance remains a major cause of chemotherapy failure in cervical cancer. Although our previous work identified that SOX4 promotes cisplatin resistance in cervical cancer cells, the underlying mechanism has not been fully elucidated. Here, we demonstrated that SOX4 not only induces resistance to cisplatin but also to oxaliplatin and carboplatin, suggesting its potential role as a multidrug resistance gene. Overexpression of SOX4 markedly suppressed glycolytic activity in cervical cancer cells and induced cisplatin resistance by inhibiting both the intrinsic and extrinsic apoptotic pathways. Rescue and neutralization experiments further indicated that SOX4 upregulates SIRT1, which subsequently represses the expression of GLUT1 on the cell membrane. This suppression leads to diminished cellular glucose uptake, resulting in decreased glycolysis and overall metabolic activity. Given that cisplatin preferentially targets highly proliferating cells, SOX4-driven metabolic deceleration enables cervical cancer cells to evade cisplatin-mediated cytotoxicity. Together, these findings demonstrate that SOX4 enhances cisplatin resistance in cervical cancer through SIRT1-upregulated suppression of glycolysis.
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Funding
This work was supported by the Key Scientific and Technological Projects of Henan Province (Grant No. 252102311135); the Key Scientific Research Projects of Higher Education Institutions in Henan Province (Grant No. 25A320018, 25A320020); the Natural Science Foundation of Henan (Grant No. 242300420119, 242300420123); the 111 Project (Grant No. D20036).
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RLS was responsible for funding acquisition, project administration, study design and experimental operation. HFG performed experimental operation, data analysis and manuscript drafting. RZ and HYL conducted experimental operation and literature investigation. HJY revised the manuscript. XFZ provided resources and materials. XLQ provided funding support. JL was responsible for study design. QZW conducted final review and editing, and provided funding support.
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Sun, R., Gong, H., Zhao, R. et al. SOX4 induces cisplatin resistance in cervical cancer cells by inhibiting aerobic glycolysis. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02954-x
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DOI: https://doi.org/10.1038/s41420-026-02954-x
