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Peer-reviewedCC BY-NC-NDNature communications

Structural and mechanistic insights into OCTN1-mediated transport and cancer cell proliferation.

  • Binghong Xu1
  • Shengjian Liang2,3
  • Ziyu Wang4
  • Xiaoyu Zhou4
  • Liuying Wang4
  • Qinqin Liang4
  • Xiaoke Liu2,3
  • Wei Guo4
  • Sai Shi5,6
  • Cheng Zhu7
  • Sheng Ye8
  • Zhiyong Lou9,10
1 more authors
  • Yaxin Wang11,12
12 affiliations
  1. 1State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin, China. [email protected].
  2. 2Pathogen and Anti-Infection Technology Innovation Center, Yanzhao Advanced Biotechnology and Medicine Laboratory, Institute of Tsinghua University, Hebei, China.
  3. 3School of Basic Medical Sciences, Tsinghua University, Beijing, China.
  4. 4State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin, China.
  5. 5State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin, China. [email protected].
  6. 6Department of Medical and Pharmaceutical Informatics, Hebei Medical University, Shijiazhuang, China. [email protected].
  7. 7State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin, China. [email protected].
  8. 8State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin, China. [email protected].
  9. 9Pathogen and Anti-Infection Technology Innovation Center, Yanzhao Advanced Biotechnology and Medicine Laboratory, Institute of Tsinghua University, Hebei, China. [email protected].
  10. 10School of Basic Medical Sciences, Tsinghua University, Beijing, China. [email protected].
  11. 11State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin, China. [email protected].
  12. 12Pathogen and Anti-Infection Technology Innovation Center, Yanzhao Advanced Biotechnology and Medicine Laboratory, Institute of Tsinghua University, Hebei, China. [email protected].
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Abstract

The Novel Organic Cation Transporter 1 (OCTN1) facilitates the uptake of endogenous metabolites and therapeutic drugs across diverse tissues. Recognized as a key transporter for the antioxidant ergothioneine (ET), OCTN1 also mediates the cellular entry and release of various cationic compounds. Dysregulation of OCTN1 has been implicated in cancer progression and drug interaction. In non-neuronal systems, OCTN1-mediated acetylcholine (ACh) transport has been implicated in promoting cancer progression by enhancing tumor cell proliferation and invasion. Despite its physiological and clinical relevance, the structural mechanisms underlying substrate recognition and transport by OCTN1 have remained poorly understood. Here, we present cryo-EM structures of human OCTN1 in both apo and ET-bound states, revealing the binding site of ET and elucidating conformational changes essential for sodium-dependent substrate transport. Furthermore, structure-based virtual screening identified mebendazole (MBZ) as a potent inhibitor targeting OCTN1, effectively suppressing the proliferation of cervical and lung cancer cells. Our findings provide a structural framework for understanding OCTN1 function and inform strategies to target this transporter in cancer.

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Cite

BibTeXRIS
BibTeX
@article{xu2026structural,
  title = {{Structural and mechanistic insights into OCTN1-mediated transport and cancer cell proliferation.}},
  author = {Binghong Xu and Shengjian Liang and Ziyu Wang and Xiaoyu Zhou and Liuying Wang and Qinqin Liang and Xiaoke Liu and Wei Guo and Sai Shi and Cheng Zhu and Sheng Ye and Zhiyong Lou and Yaxin Wang},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77727-2},
  url = {https://europepmc.org/article/MED/42875455},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Structural and mechanistic insights into OCTN1-mediated transport and cancer cell proliferation.
AU  - Binghong Xu
AU  - Shengjian Liang
AU  - Ziyu Wang
AU  - Xiaoyu Zhou
AU  - Liuying Wang
AU  - Qinqin Liang
AU  - Xiaoke Liu
AU  - Wei Guo
AU  - Sai Shi
AU  - Cheng Zhu
AU  - Sheng Ye
AU  - Zhiyong Lou
AU  - Yaxin Wang
PY  - 2026
DA  - 2026/09/14
JO  - Nature communications
DO  - 10.1038/s41467-026-77727-2
UR  - https://europepmc.org/article/MED/42875455
AB  - The Novel Organic Cation Transporter 1 (OCTN1) facilitates the uptake of endogenous metabolites and therapeutic drugs across diverse tissues. Recognized as a key transporter for the antioxidant ergothioneine (ET), OCTN1 also mediates the cellular entry and release of various cationic compounds. Dysregulation of OCTN1 has been implicated in cancer progression and drug interaction. In non-neuronal systems, OCTN1-mediated acetylcholine (ACh) transport has been implicated in promoting cancer progression by enhancing tumor cell proliferation and invasion. Despite its physiological and clinical relevance, the structural mechanisms underlying substrate recognition and transport by OCTN1 have remained poorly understood. Here, we present cryo-EM structures of human OCTN1 in both apo and ET-bound states, revealing the binding site of ET and elucidating conformational changes essential for sodium-dependent substrate transport. Furthermore, structure-based virtual screening identified mebendazole (MBZ) as a potent inhibitor targeting OCTN1, effectively suppressing the proliferation of cervical and lung cancer cells. Our findings provide a structural framework for understanding OCTN1 function and inform strategies to target this transporter in cancer.
SN  - 2041-1723
ER  -