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Methionine metabolite spermidine inhibits tumor pyroptosis by enhancing MYO6-mediated endocytosis

Author

Listed:
  • Jiawei Wu

    (Sun Yat-sen University Cancer Center
    Sun Yat-Sen University Cancer Center)

  • Cong Ding

    (Sun Yat-sen University Cancer Center
    Sun Yat-Sen University Cancer Center)

  • Chuqing Zhang

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Zhimin Xu

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Zhenji Deng

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Hanmiao Wei

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Tingxiang He

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Liufen Long

    (Sun Yat-sen University Cancer Center)

  • Linglong Tang

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Jun Ma

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

  • Xiaoyu Liang

    (Sun Yat-sen University Cancer Center
    Sun Yat-sen University Cancer Center)

Abstract

The connection between amino acid metabolism and pyroptosis remains elusive. Herein, we screen the effect of individual amino acid on pyroptosis and identify that methionine inhibits GSDME-mediated pyroptosis. Mechanistic analyses unveil that MYO6, a unique actin-based motor protein, bridges the GSDME N-terminus (GSDME-NT) and the endocytic adaptor AP2, mediating endolysosomal degradation of GSDME-NT. This degradation is increased by the methionine-derived metabolite spermidine noncanonically by direct binding to MYO6, which enhances MYO6 selectivity for GSDME-NT. Moreover, combination targeted therapies using dietary or pharmacological inhibition in methionine-to-spermidine metabolism in the tumor promotes pyroptosis and anti-tumor immunity, leading to a stronger tumor-suppressive effect in in vivo models. Clinically, higher levels of tumor spermidine and expression of methionine-to-spermidine metabolism-related gene signature predict poorer survival. Conclusively, our research identifies an unrecognized mechanism of pyroptotic resistance mediated by methionine-spermidine metabolic axis, providing a fresh angle for cancer treatment.

Suggested Citation

  • Jiawei Wu & Cong Ding & Chuqing Zhang & Zhimin Xu & Zhenji Deng & Hanmiao Wei & Tingxiang He & Liufen Long & Linglong Tang & Jun Ma & Xiaoyu Liang, 2025. "Methionine metabolite spermidine inhibits tumor pyroptosis by enhancing MYO6-mediated endocytosis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57511-4
    DOI: 10.1038/s41467-025-57511-4
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