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

Jiawei Wu, Cong Ding, Chuqing Zhang, Zhimin Xu, Zhenji Deng, Hanmiao Wei, Tingxiang He, Liufen Long, Linglong Tang (), Jun Ma () and Xiaoyu Liang ()
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Jiawei Wu: Sun Yat-sen University Cancer Center
Cong Ding: Sun Yat-sen University Cancer Center
Chuqing Zhang: Sun Yat-sen University Cancer Center
Zhimin Xu: Sun Yat-sen University Cancer Center
Zhenji Deng: Sun Yat-sen University Cancer Center
Hanmiao Wei: Sun Yat-sen University Cancer Center
Tingxiang He: Sun Yat-sen University Cancer Center
Liufen Long: Sun Yat-sen University Cancer Center
Linglong Tang: Sun Yat-sen University Cancer Center
Jun Ma: Sun Yat-sen University Cancer Center
Xiaoyu Liang: Sun Yat-sen University Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57511-4

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