Abstract
Intrahepatic cholangiocarcinoma (ICC) is a major contributor to cancer-related mortality on a global scale, yet it suffers from a lack of reliable early diagnostic biomarkers and effective therapeutic targets. Pemigatinib has been identified as a therapeutic option for advanced ICC; however, its long-term clinical efficacy is significantly hindered by the development of drug resistance. To address this, pemigatinib-resistant ICC cells were established by culturing with increasing drug treatment. 98 pairs of ICC tissue samples were collected and analyzed to assess the association between β-arrestin 2 (ARRB2) and ICC progression. The role and mechanism of ARRB2 in the malignant progression of ICC and resistance to pemigatinib were explored in vitro and in vivo experiments. The results demonstrated that ARRB2 expression is markedly upregulated in pemigatinib-resistant ICC cells compared to their parental counterparts. Suppression of ARRB2 expression markedly attenuated ICC chemoresistance to pemigatinib. Clinical data further verified that ARRB2 is correlated with poorer pathological stage and prognosis in ICC patients. Mechanistic studies revealed that ARRB2 activation in ICC is mediated by METTL3-dependent m6A methylation. Functional analyses demonstrated that ARRB2 promotes the malignant progression of ICC by facilitating YAP nuclear translocation while also modulating the sensitivity of ICC to pemigatinib through the Raf-MEK-ERK signaling axis. This study identifies the tumor-promoting activities of ARRB2 and elucidates the regulatory mechanism of the METTL3-ARRB2-YAP/Raf axis in ICC, which may provide a novel prognostic biomarker and potential therapeutic target for human ICC.
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All the data needed to evaluate the conclusions in the paper are presented in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (grants 82270688, 82370663, 82400742) and China Postdoctoral Science Foundation (grant 2025M772338).
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Genshu Wang, Shuguang Zhu, Xijing Yan and Hui Li designed this study; Haoqi Chen, Xiaowen Wang, Wenfeng Zhu, Wenjie Zheng, Qiwei Yang, Zhixing Liang, Yuan Zhang and Xuejiao Li performed the experiments; Xiaolong Chen and Jinliang Liang analyzed and interpreted the data; Haoqi Chen and Xijing Yan drafted the manuscript; Genshu Wang, Shuguang Zhu, Hua Li and Linsen Ye supervised the study. All the authors read and approved the final manuscript.
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This study was approved by the Ethical Committee of the Third Affiliated Hospital of Sun Yat-sen University. And the animal experiments were approved by the South China Agricultural University Animal Ethics Committee.
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All human tissue specimens, including ICC tissues and ANTs, were obtained with written informed consent provided by all enrolled cases.
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Chen, H., Wang, X., Zhu, W. et al. N6-methyladenosine–mediated up-regulation of ARRB2 regulates intrahepatic cholangiocarcinoma malignant progression and pemigatinib resistance through MAPK and Hippo signaling pathways. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08574-8
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DOI: https://doi.org/10.1038/s41419-026-08574-8
