EXOSC4 as a novel regulator of neddylation in acute myeloid leukemia

Acute myeloid leukaemia (AML) is a common haematological malignancy with an unsatisfactory prognosis despite recent therapeutic advances. Neddylation and ferroptosis have been implicated in the regulation of malignant cell proliferation, survival and therapy response. However, the relationship between neddylation-related dysregulation and ferroptosis-associated pathways in AML remains poorly understood. Transcriptomic data from TCGA-AML and GTEx normal controls were integrated for differential expression and functional enrichment analyses. Prognostic neddylation-related genes were identified using univariate Cox regression, LASSO regression and multivariate Cox regression analyses. The expression and regulatory association of EXOSC4 with NEDD8 and Cullin1 neddylation were validated in clinical samples and AML cell lines using qRT-PCR and Western blotting. CCK-8 assays were performed to evaluate the effects of EXOSC4 overexpression, MLN4924, erastin and Ferrostatin-1 on AML cell viability. A ceRNA regulatory network was constructed based on the key neddylation-related genes. GO and KEGG enrichment analyses showed that differentially expressed neddylation-related genes were mainly enriched in post-translational modification-related biological processes and pathways. Cox regression analyses identified EXOSC4 as a prognostic neddylation-related gene significantly associated with AML prognosis. Validation in clinical samples showed that EXOSC4 and NEDD8 were differentially expressed at both the mRNA and protein levels. In vitro experiments further showed that EXOSC4 expression was positively associated with NEDD8 protein levels and Cullin1 neddylation, suggesting that EXOSC4 may be involved in neddylation-related regulation in AML. Correlation analysis indicated a potential association between neddylation-related dysregulation and ferroptosis-associated pathways. Moreover, CCK-8 assays showed that EXOSC4 overexpression enhanced AML cell viability, whereas MLN4924 suppressed this effect and further enhanced erastin-induced reduction in cell viability, suggesting a potential role of EXOSC4 in ferroptosis-related cellular responses. In conclusion, this study reveals a potential association between neddylation-related dysregulation and ferroptosis-associated pathways in AML. EXOSC4 was identified as a candidate regulatory molecule that may connect neddylation activity with ferroptosis-related cellular responses. These findings provide new insights into the molecular mechanisms of AML and support further investigation of EXOSC4 as a potential therapeutic target.