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Transport mechanism and drug discovery of human monocarboxylate transporter 1

Acta Pharmacologica Sinica volume 46, pages 2323–2333 (2025)Cite this article

Abstract

Human monocarboxylate transporters (MCTs) are crucial for tumour cell glycolysis. Inhibiting MCT-mediated lactate transport can suppress the proliferation of solid tumours and enhance the efficacy of the immune system against tumours. Despite the importance of this transporter, the molecular mechanism of lactate transport by MCT1 remains elusive, hindering the development of targeted therapies. Here, we used principal component analysis to elucidate the allosteric mechanisms of the MCT family. Enhanced sampling revealed that specific residue pairs (E46-K289 and E376-R143) are essential for maintaining the inwards and outwards conformations of MCT1. Quantum chemical calculations and umbrella sampling demonstrated that lactate molecules and protons are co-transported sequentially, with K38 and R313 playing key roles in lactate translocation. On the basis of these data, we conducted a drug screening campaign targeting the core pocket of MCT1 and identified silybin as a selective MCT1 inhibitor. Silybin had significant inhibitory effects on tumour cells with high MCT1 expression. These findings provide a comprehensive understanding of the lactate transport mechanism of MCT1 and lay the groundwork for the rational design of antitumour drugs targeting MCT1.

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Fig. 1: The dominant allosteric motion that MCTs undergo during state transition.
Fig. 2: Interaction model analysis of the dynamic transition of MCT1.
Fig. 3: Molecular mechanisms of MCT1 transport of substrates.
Fig. 4: Virtual screening revealed that silybin significantly inhibited MCT1 activity.
Fig. 5: Interaction mode between silybin and MCT1.
Fig. 6: Inhibitory potency of silybin on cancer cells with high expression of MCT1.
Fig. 7: Silybin inhibits the growth of tumours in vivo.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 82404583 to SS). Hebei Province Yanzhao Golden Platform Talent Gathering Plan Backbone Talent Project (Education Platform) (Grant No. HJYB202524 to SS). Ministry of Science and Technology (2024YFA0916800 to BHX, 2020YFA0908500 to SY, 2024YFC3407300 to YXW). The Independent Innovation Fund of Tianjin University (2023XQM-0050 to BHX). We thank the Haihe Laboratory of Sustainable Chemical Transformations for financial support. This research was supported by the Medical Science Data Center of Hebei Medical University.

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Author notes

  1. These authors contributed equally: Sai Shi, Jia-chen Li, Xiao-yu Zhou

Authors and Affiliations

  1. Department of Medical and Pharmaceutical Informatics, Hebei Medical University, Shijiazhuang, 050011, China

    Sai Shi

  2. Frontiers Science Center for Synthetic Biology (Ministry of Education), Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, 300072, China

    Sai Shi, Jia-chen Li, Xiao-yu Zhou, Zhen-lu Li, Ya-xin Wang, Bing-hong Xu & Sheng Ye

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Contributions

SS: conceptualization, methodology, writing - original draft. JCL: investigation, validation. XYZ: data curation. ZLL: methodology. YXW: formal analysis, supervision. BHX: resources, writing - original draft. SY: project administration, writing - original draft.

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Correspondence to Zhen-lu Li, Ya-xin Wang, Bing-hong Xu or Sheng Ye.

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Shi, S., Li, Jc., Zhou, Xy. et al. Transport mechanism and drug discovery of human monocarboxylate transporter 1. Acta Pharmacol Sin 46, 2323–2333 (2025). https://doi.org/10.1038/s41401-025-01517-7

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