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

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

SUBMITTER: Wu J 

PROVIDER: S-EPMC11880502 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature