Abstract
Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck. Early-stage OSCC is primarily treated using surgery; advanced-stage OSCC is managed using a multidisciplinary approach, including surgery combined with adjuvant radiotherapy and chemotherapy. However, tumor recurrence and metastasis remain major challenges, with a 5-year survival rate of ~50%. Dysregulation of transcription factors is associated with the pathogenesis of various cancers. This study focused on the role of ZIC2, a member of the zinc finger protein family, in OSCC. ZIC2 was identified as a prognostically relevant transcription factor in OSCC through bioinformatic analysis, showing high expression in OSCC and association with poor prognosis in patients. In vitro and in vivo, ZIC2 knockdown inhibited the proliferation, migration, invasion, and spheroid formation ability of OSCC cells and restored their sensitivity to chemotherapeutic drugs; overexpression of ZIC2 showed the opposite effect. RNA-seq and targeted metabolomics analyses revealed that in OSCC cells with zic2 knockdown, the expression of glycerophosphocholine (GPC) and the key rate-limiting enzyme LYPLA2 was decreased. LYPLA2 overexpression rescued the effects of ZIC2 knockdown on the proliferation, migration, and invasion of OSCC cells. GPC increased the stemness of OSCC tumor cells; ZIC2-regulated GPC metabolism through LYPLA2, inducing changes in the expression of the cancer stem cell markers Nanog and OCT4. In conclusion, we identified ZIC2 as an OSCC stemness-related gene, a potential therapeutic target for OSCC, providing new insights for treating OSCC.
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Data availability
The RNA-seq data have been deposited in the GEO database (GSE304366). The results of targeted metabolomics are provided in the supplementary materials 5, and detailed information can be obtained by contacting the corresponding author.
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Acknowledgements
We would like to express our gratitude to Dr. Jingcun Shi, Dr. Ruiyu Guo, Dr. Huasheng Li, Dr. Lu Zhao, Dr. Mei Zhang and Dr. Hexin Ma from the Shanghai Key Laboratory of Stomatology for their assistance in this study. We also thank the staff of the TCGA project team and the GEO project team for providing public data.
Funding
This study was supported by the Project of Central Government Guiding Local Scientific and Technological Development Funds in Hebei Province (Project no.: 246Z7728G), the Key Project of the Joint Fund for Precision Medicine Innovation and Development (Project no.: H2025206023), the Excellent Clinical Medicine Talents Training Project Funded by the Government in 2024 (Project no.: ZF2024148), and the Excellent Clinical Medicine Talents Training Project Funded by the Government in 2025 (Project no.: ZF2025241).
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Siyi Li and Xingyue Ma designed the experiments, completed most of the experimental work, and wrote the manuscript. Ming Yan, Longwei Hu, and Ran Li provided experimental guidance. Xingyue Ma and Yuantao Li conducted the animal experiments. Haiyang Li and Bowen Wang assisted in completing the molecular biology experiments. Jianping Liu and Xiaoyan Zhang carried out the data analysis. Shuang Mei and Xiangjun Li revised the manuscript and supervised the research.
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This study has been approved by the Ethics Committee of the Stomatological Hospital of Hebei Medical University, and written informed consent has been collected from each patient with OSCC. The animal experiment has been approved by the Laboratory Animal Welfare and Ethics Committee of Hebei Medical University (Laboratory Animal Use License no.: SYXK(Ji)2020-002), and all experiments have been carried out in accordance with the guiding principles and relevant laws.
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Li, S., Ma, X., Li, Y. et al. ZIC2 affects oral squamous cell carcinoma stemness by regulating glycerophosphocholine metabolism via LYPLA2. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08483-w
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DOI: https://doi.org/10.1038/s41419-026-08483-w
