Methionine restriction inhibits EZH2-mediated GSDMD methylation to promote pyroptosis in prostate cancer.

EZH2 directly methylates GSDMD at lysine 168 to suppress caspase-1 cleavage, and methionine deprivation plus GSK126 overcomes this blockade to promote pyroptosis in prostate cancer models.

• Why it matters: EZH2 inhibitors show limited clinical efficacy, and the field lacks a clear mechanism linking EZH2 activity to pyroptosis control in prostate cancer.
• What they did: The study used prostate cancer cells and clinical specimens to test EZH2’s posttranslational effect on GSDMD, then assessed pyroptosis and tumor growth in vivo with methionine deprivation and the EZH2 inhibitor GSK126.
• The result: EZH2 inhibition increased GSDMD-dependent pyroptosis, clinical samples showed an inverse relationship between EZH2 and cleaved GSDMD (GSDMD-N), and methionine deprivation combined with GSK126 enhanced pyroptosis and suppressed tumor growth in vivo.

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