Fingolimod overcomes cisplatin resistance in esophageal squamous cell carcinoma by targeting NUP54 to disrupt homologous recombination repair.
9 affiliations
- 1Shaanxi Key Laboratory of Research and Utilization of Resource Plants on the Loess Plateau, College of Life Sciences, Yan'an University, Yan'an, China.
- 2Department of Pathology, Xijing Hospital, School of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.
- 3Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- 4Department of Clinical Medicine, School of Medicine, Yan'an University, Yan'an, China.
- 5Department of Life Sciences, Aberystwyth University, Aberystwyth, UK.
- 6Department of Neurosurgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, 110016, China. [email protected].
- 7The South Campus of the Sixth People's Hospital, Shanghai University of Medicine & Health Sciences, No. 6600 Nanfeng Highway, Shanghai, 201400, China. [email protected].
- 8Department of Reproductive Medicine, Xi'an International Medical Center Hospital, Northwest University, 777 Xitai Road, Xi'an, 710100, China. [email protected].
- 9Department of Pathology, Xijing Hospital, School of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China. [email protected].
Abstract
Cisplatin resistance is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). To address this challenge, we screened a U.S. Food and Drug Administration (FDA)-approved drug library and identified fingolimod, an immunomodulatory agent, as a potent inhibitor of cisplatin-resistant ESCC cells. Fingolimod is likely to directly binds to Glu266 of the nuclear pore complex protein NUP54, promoting its proteasomal degradation. This disrupts the NUP54-NUP58-NUP62 central channel, impairing the nuclear import of the key DNA repair protein SPIDR. Consequently, fingolimod treatment inhibits the recruitment of the SPIDR-RAD51-DMC1 complex by chromatin, causing defective homologous recombination repair, accumulation of DNA damage, and ultimately, the reversal of cisplatin resistance. In addition, fingolimod restored the sensitivity of cisplatin to ESCC treatment in both patient-derived xenograft and organoid models. Our study unveils a novel mechanism by which fingolimod targets the nuclear pore complex to suppress DNA repair, providing a compelling rationale for repurposing fingolimod as a combination therapy to overcome cisplatin resistance in ESCC.
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BibTeX
@article{cao2026fingolimod,
title = {{Fingolimod overcomes cisplatin resistance in esophageal squamous cell carcinoma by targeting NUP54 to disrupt homologous recombination repair.}},
author = {Duo Cao and Jin Liu and Guoliang Chen and Tianqi Xu and Xiangru Zhou and Junpeng Xu and Pusong Zhao and Peng Wang and Xinya Yang and Luis A J Mur and Ligang Chen and Zhenliang Sun and Qingge Jia and Mingyang Li},
journal = {Cell communication and signaling : CCS},
year = {2026},
month = aug,
doi = {10.1186/s12964-026-03113-6},
url = {https://europepmc.org/article/MED/42958413},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Fingolimod overcomes cisplatin resistance in esophageal squamous cell carcinoma by targeting NUP54 to disrupt homologous recombination repair.
AU - Duo Cao
AU - Jin Liu
AU - Guoliang Chen
AU - Tianqi Xu
AU - Xiangru Zhou
AU - Junpeng Xu
AU - Pusong Zhao
AU - Peng Wang
AU - Xinya Yang
AU - Luis A J Mur
AU - Ligang Chen
AU - Zhenliang Sun
AU - Qingge Jia
AU - Mingyang Li
PY - 2026
DA - 2026/08/01
JO - Cell communication and signaling : CCS
DO - 10.1186/s12964-026-03113-6
UR - https://europepmc.org/article/MED/42958413
AB - Cisplatin resistance is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). To address this challenge, we screened a U.S. Food and Drug Administration (FDA)-approved drug library and identified fingolimod, an immunomodulatory agent, as a potent inhibitor of cisplatin-resistant ESCC cells. Fingolimod is likely to directly binds to Glu266 of the nuclear pore complex protein NUP54, promoting its proteasomal degradation. This disrupts the NUP54-NUP58-NUP62 central channel, impairing the nuclear import of the key DNA repair protein SPIDR. Consequently, fingolimod treatment inhibits the recruitment of the SPIDR-RAD51-DMC1 complex by chromatin, causing defective homologous recombination repair, accumulation of DNA damage, and ultimately, the reversal of cisplatin resistance. In addition, fingolimod restored the sensitivity of cisplatin to ESCC treatment in both patient-derived xenograft and organoid models. Our study unveils a novel mechanism by which fingolimod targets the nuclear pore complex to suppress DNA repair, providing a compelling rationale for repurposing fingolimod as a combination therapy to overcome cisplatin resistance in ESCC.
SN - 1478-811X
ER -