Abstract ZFTA-RELA ependymomas are highly aggressive brain tumors with significant mortality. These tumors are characterized by the oncogenic fusion of a putative chromatin remodeler ZFTA and the NFκB effector RELA. Using a comprehensive metabolic screen, we discovered that ZFTA-RELA cells generate itaconate, a metabolite linked to the TCA cycle. Although itaconate is a well-known immunomodulatory metabolite produced by macrophages, its production and function within tumor cells have been unclear. We found that itaconate is synthesized by Aconitate Decarboxylase-1 (ACOD1), and that ZFTA-RELA induces ACOD1 expression in an NFκB-dependent manner. Itaconate production in turn supports a coupled metabolic-epigenetic feed-forward loop that sustains pathogenic ZFTA-RELA fusion expression through H3K4me3-dependent, epigenetic activation. To provide the metabolic input required for itaconate synthesis, ZFTA-RELA tumors suppress PTEN expression to activate PI3K/AKT signaling pathway. The increased glutaminolysis in these tumors supplied the carbon needed for itaconate generation. As a result, inhibiting glutamine metabolism reduces pathogenic ZFTA-RELA levels and shows strong therapeutic efficacy in multiple in vivo models. Moreover, combining glutamine antagonists with PI3K/mTOR inhibitors prevents spinal metastasis. Overall, our findings show that ZFTA-RELA ependymomas hijack the macrophage-associated itaconate metabolic pathway to epigenetically reinforce expression of the ZFTA-RELA fusion driver, identifying itaconate as an oncometabolite. These results highlight itaconate upregulation as an unrecognized driver of ZFTA-RELA ependymoma and point to new therapeutic avenues for children affected by this devastating disease, while broadening our understanding of oncometabolites as a distinct class of cancer dependencies. Citation Format: Siva Kumar Natarajan, Joanna Lum, James Haggerty-Skeans, Minal Nenwani, Sanjana Eyunni, Mateus Mota, Jill Bayliss, Akash Deogharkar, Erin Hamanishi, Simon Hoffman, Eleanor Young, Qiuyang Zhang, Rijul Mehta, Abhijit Parolia, Peter Sajjakulnukit, Robert Doherty, Carl Koschmann, Arul M. Chinnaiyan, Costas Andreas Lyssiotis, Deepak Nagrath, Sriram Venneti. Itaconate acts as an oncometabolite to drive lethal pediatric ependymomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3285.
Natarajan et al. (Fri,) studied this question.