密歇根大学医学院Sriram Venneti小组的最新研究揭示了ZFTA-RELA室管膜瘤通过表观遗传驱动融合表达。该项研究成果发表在2026年2月4日出版的《自然》上。

在这里，研究小组发现ZFTA–RELA⁺细胞产生衣康酸，一种关键的巨噬细胞相关免疫调节代谢物。衣康酸是由顺式乌康酸脱羧酶1 （ACOD1，也称为IRG1）生成的。

然而，肿瘤细胞产生衣康酸及其在肿瘤中的内在作用尚不清楚。ACOD1以依赖于ZFTA–RELA的方式上调。在功能上，衣康酸钠能够建立一个前馈系统，对维持致病性ZFTA–RELA水平至关重要。衣康酸盐通过抑制H3K4me3去甲基化酶KDM5，通过富集激活H3K4me3，从表观遗传上激活ZFTA-RELA转录。ZFTA-RELA ⁺肿瘤促进谷氨酰胺代谢，为衣康酸合成提供碳。ACOD1或谷氨酰胺代谢的拮抗作用可降低致病性ZFTA-RELA水平，在多种体内模型中具有有效的治疗作用。从机制上讲，ZFTA-RELA通过表观遗传抑制PTEN的表达来上调PI3K-mTOR信号传导，PI3K-mTOR信号传导是谷氨酰胺水解的已知驱动因素。最后，抑制ACOD1或谷氨酰胺拮抗剂联合抑制PI3K-mTOR可消除脊柱转移。

他们的数据表明，ZFTA–RELA⁺室管膜瘤破坏巨噬细胞样衣康酸代谢途径，以维持ZFTA–RELA驱动因子的表达，这意味着衣康酸是一种候选的肿瘤代谢物。综上所述，他们的结果表明，衣康酸上调是以前未被认识到的ZFTA–RELA⁺室管膜瘤的驱动因素。他们的工作对未来的药物开发具有重要意义，可以减少这种脑肿瘤的致病性ZFTA–RELA表达，并将促进他们对肿瘤代谢物作为癌症治疗依赖的新类别的理解。

据悉，ZFTA–RELA⁺室管膜瘤是一种恶性脑肿瘤，由染色质重塑剂ZFTA和NF-κB介质RELA1之间形成的离子定义。

附：英文原文

Title: ZFTA–RELA ependymomas make itaconate to epigenetically drive fusion expression

Author: Natarajan, Siva Kumar, Lum, Joanna, Skeans, James Haggerty, Nenwani, Minal, Eyunni, Sanjana, Mota, Mateus, Bayliss, Jill M., Deogharkar, Akash, Hamanishi, Erin Taya, Pun, Matthew, Sweha, Stefan R., Hoffman, Simon, Young, Eleanor, Zhang, Qiuyang, Mehta, Rijul, Animasahun, Olamide, Narayanan, Pranav, Sunil, Sushanth, Parolia, Abhijit, Sajjakulnukit, Peter, Panwalkar, Pooja, Doherty, Robert, Clausen, Madison, Dang, Derek, Hawes, Debra, Yang, Fusheng, Santi, Mariarita, Judkins, Alexander R., Wilson, Yelena, Vigil, Thomas, Franson, Andrea, Mortensen, Richard M., Ozawa, Tatsuya, Griesinger, Andrea, Holland, Eric C., Foreman, Nicholas K., Michealraj, Kulandaimanuvel Antony, Agnihotri, Sameer, Taylor, Michael, Gilbertson, Richard J., Koschmann, Carl, Chinnaiyan, Arul M., Lyssiotis, Costas A., Nagrath, Deepak, Venneti, Sriram

Issue&Volume: 2026-02-04

Abstract: ZFTA–RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA–RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA–RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA–RELA levels. Itaconate epigenetically activates ZFTA–RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA–RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA–RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA–RELA epigenetically suppresses PTEN expression to upregulate PI3K–mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K–mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA–RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA–RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA–RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA–RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

DOI: 10.1038/s41586-025-10005-1

Source: https://www.nature.com/articles/s41586-025-10005-1