Abstract
Intrahepatic cholangiocarcinoma (CCA) is a highly aggressive malignancy arising from the intrahepatic biliary epithelium with insidious onset and dismal clinical outcomes. The lack of reliable early diagnostic markers and effective therapeutic targets underscores the urgent need for novel intervention strategies. Integrated evaluation of public transcriptomic datasets and local validation cohort with survival analysis were performed to assess expression pattern and prognostic significance of cystatin SN (CST1) in CCA. Functional characterization was performed via gain- and loss-of-function experiments in HuCCT1 and RBE cells, complemented by murine orthotopic liver implantation and pulmonary metastasis models. We found that CST1 was significantly upregulated in human CCA tissues. Elevated CST1 expression predicted unfavorable prognosis in CCA patients. Subsequently functional studies revealed that overexpression of CST1 suppressed cellular senescence markers, as evidenced by decreased senescence-associated β-galactosidase activity and downregulated senescence-associated secretory phenotype factors (IL-6, CCL20). Concomitantly, CST1 overexpression enhanced cell proliferation, migration, invasion, and in vivo metastatic capacity. Integrated multi-omics profiling identified CST1-mediated suppression of pyrimidine metabolism through TYMS downregulation. However, exogenous thymidine supplementation failed to rescue proliferation defects upon CST1 knockdown, indicating that CST1-promoted tumor growth is independent of pyrimidine metabolism. Mechanistically, NFATC2 transcriptionally activates CST1, which subsequently abrogates senescence through SOX4 stabilization; ectopic SOX4 expression rescues senescence induced by CST1 depletion. These findings establish CST1 as a promising therapeutic target and provide mechanistic insights for CCA intervention strategies.
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The datasets used during the current study are available from the corresponding author on reasonable request.
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This research was supported by the Natural Science Foundation of Shandong Province (grant number ZR2021MH069).
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WZ: Conceptualization, formal analysis, writing-original draft, funding acquisition; JZ: Writing-review & editing, Resources, Validation; KL, JS, LC, and GY: Investigation.
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Clinical experimental protocols were approved by the Ethical and Scientific Committees of Affiliated Hospital of Qingdao University. All animal works were performed following National Research Council: Guide for the Care and Use of Laboratory Animals, and approved by the Animal Experimentation Ethics Committee of Affiliated Hospital of Qingdao University.
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Zhao, W., Zhao, J., Li, K. et al. NFATC2-mediated CST1 upregulation drives cholangiocarcinoma growth and metastasis. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03036-8
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DOI: https://doi.org/10.1038/s41420-026-03036-8
