Background <p>Tumour necrosis factor receptor-associated factor 7 (TRAF7), an E3 ubiquitin ligase, regulates multiple signalling pathways through posttranslational modifications. However, its role in acute myeloid leukaemia (AML) remains controversial and poorly understood.</p> Methods <p>Analysis of public AML datasets and validation using in-house samples were conducted to evaluate TRAF7 expression in bone marrow samples from AML patients and to assess its potential as a prognostic marker. Gain- and loss-of-function studies were performed in AML cell lines, primary CD34⁺ cells and a xenograft mouse model to characterize the role of TRAF7 in AML. RNA sequencing was employed to elucidate the mechanisms underlying the pro-leukaemic activity of TRAF7, and a ubiquitination assay was used to identify the substrate of TRAF7.</p> Results <p>TRAF7 is highly expressed in AML, particularly in the M5 subtype, and its upregulation serves as a novel independent prognostic marker for poor clinical outcomes. Functional studies demonstrate that TRAF7 promotes AML cell proliferation in vitro and leukaemogenesis in a human AML xenograft model. Mechanistically, TRAF7 interacts with TWIST1 and mediates its K63-linked polyubiquitination, enhancing TWIST1 nuclear localization. TWIST1 directly transcriptionally activates P2RX1, which increases mitochondrial calcium levels, respiratory activity, and ATP production, thereby fuelling leukaemic growth.</p> Conclusions <p>Taken together, our study identifies TRAF7 as a novel tumour promoter in AML via the TWIST1–P2RX1-calcium axis, highlighting its role as a prognostic biomarker. Although TRAF7 represents a potential therapeutic target, its clinical applicability remains hypothetical in the absence of direct inhibitor studies.</p> Graphical Abstract <p></p>