Abstract
Gemcitabine is a cornerstone chemotherapeutic for pancreatic ductal adenocarcinoma (PDAC); however, the frequent development of resistance compromises its efficacy and poses a significant challenge to patient prognosis. Here, we report that nuclear pore protein NUP93 is upregulated in PDAC and correlates with poor patient survival. Functional studies demonstrated that NUP93 promotes PDAC cell proliferation and confers gemcitabine resistance by enhancing DNA damage repair. Mechanistically, NUP93 interacts with the transcription factor SOX2 by recognizing its nuclear localization sequence and facilitates its nuclear import. Nuclear SOX2 transcriptionally activates the key stress granule component G3BP1 by directly binding to its promoter. Subsequently, G3BP1 stabilizes the mRNA of RAD51, a crucial homologous recombination repair factor, thereby promoting DNA damage repair and gemcitabine resistance. In vivo, disruption of the NUP93/SOX2/G3BP1 axis suppressed tumor growth and synergized with gemcitabine. Our findings unveil the novel NUP93-SOX2-G3BP1 signaling axis as a critical driver of gemcitabine resistance in PDAC, presenting a promising therapeutic target for overcoming chemoresistance.
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Funding
This study was partially supported by the National Natural Science Foundation of China (No. 82472667); Taishan Scholars Young Experts Project (No. tsqn202312380); China Higher Education Innovation Fund project (No. 2024GR041); the Natural Science Foundation of Shandong Province (ZR2025MS1491).
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ZY, HS, and CX carry out the design and conception. HS, CXY, JTD, and JSC implement the methodology. HS, CXY, and JTD acquire the data. HS, CX, YC, and JSC carry out analysis and interpretation of the data. HS, CXY, and RNG conducted animal models. ZY, HS, and NXY carry out writing, review, and/or revision of the manuscript. All authors read and approved the final manuscript.
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All methods in this study were performed in accordance with the relevant guidelines and regulations. The study involving human participants was reviewed and approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (Permission No. QYFYWZLL28017). All patients provided written informed consent prior to participation. All animal experimental procedures were approved by the Committee for the Care and Use of Laboratory Animals at the Affiliated Hospital of Qingdao University (Permission No. AHQU-MAL20201016) and were carried out in compliance with the Guide for the Care and Use of Laboratory Animals (National Research Council).
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Sun, H., Yang, C., Du, J. et al. NUP93 facilitates the nuclear import of SOX2 to activate G3BP1 transcription and impairs gemcitabine response in pancreatic cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08586-4
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DOI: https://doi.org/10.1038/s41419-026-08586-4
