EZHIP (EZH inhibitory protein) functions as a negative regulator of polycomb repressive complex 2 (PRC2), inhibiting EZH1 and EZH2 methyltransferase activity and causing global reduction of the repressive histone mark H3K27me3 12. This mechanism mirrors that of the oncohistone H3K27M in diffuse midline gliomas 32. EZHIP is aberrantly overexpressed in posterior fossa group A (PFA) ependymomas, where it drives oncogenic programs by enabling H3K27ac enrichment at metabolic genes, enhancing glycolysis and TCA cycle metabolism 1. The protein also promotes neuronal-like synaptic gene programs while repressing polyamine metabolism 4. EZHIP expression creates unique three-dimensional genomic structures called TULIPs (type B ultra long-range interactions) that are characteristic of PFA ependymomas 5. Beyond pediatric brain tumors, EZHIP shows oncogenic activity in osteosarcomas, where it impedes mesenchymal differentiation and correlates with poor therapeutic response 6. EZHIP mutations occur not only in PFA ependymomas but also in rare cases of medulloblastoma and pediatric high-grade gliomas 4. The protein represents a potential therapeutic target, as metformin treatment can reduce EZHIP levels and restore H3K27me3 deposition 1.