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

EZH2 is frequently overexpressed in solid tumors, yet the clinical efficacy of its inhibitors remains limited, highlighting an urgent need to elucidate their cytotoxic mechanisms. Here, we identify EZH2 as a posttranslational suppressor of pyroptosis through direct methylation of GSDMD. We revealed that EZH2 inhibition triggered GSDMD-dependent pyroptosis in prostate cancer cells. Clinical specimens showed an inverse correlation between EZH2 levels and cleaved GSDMD (GSDMD N-terminal, GSDMD-N) levels, reinforcing its role as a negative regulator of GSDMD activation. Mechanistically, EZH2 methylated GSDMD at lysine 168, thereby blocking caspase-1-mediated cleavage and suppressing its activation. Notably, methionine deprivation overcame this blockade and combined with the EZH2 inhibitor GSK126 to enhance pyroptosis and suppress tumor growth in vivo. These findings establish the methionine-EZH2-GSDMD axis as an epigenetic-metabolic hub controlling pyroptosis via posttranslational regulation, providing a mechanistic rationale for co-targeting methionine metabolism and EZH2 in prostate cancer therapy.