Itaconate fuels ZFTA–RELA+ ependymoma by epigenetically sustaining its driver

A Nature study shows ZFTA–RELA+ ependymomas produce itaconate via ACOD1, fueling a feed-forward loop that epigenetically maintains ZFTA–RELA expression by increasing activating H3K4me3 through inhibition of the KDM5 demethylase. The tumors also upregulate glutamine metabolism to supply itaconate precursors. Blocking ACOD1 or glutamine metabolism reduces pathogenic ZFTA–RELA levels and inhibits tumor growth in cell and animal models, with combination approaches (glutamine antagonism plus PI3K–mTOR inhibition) suppressing spinal metastasis. The findings position itaconate as a potential therapeutic vulnerability in ZFTA–RELA+ ependymomas and highlight oncometabolites as treatment targets.