Disulfidptosis in pediatric AML: a multi-omics approach to risk stratification and potential therapeutic strategy.

Background: The evolving molecular portrait of acute myeloid leukemia (AML) has exposed previously unrecognized cell death programs that fuel disease progression and treatment resistance-uncovering untapped therapeutic potential. Recent work has uncovered disulfidptosis-a novel form of programmed cell death (PDC) triggered by glucose deprivation in SLC7A11-high AML cells-as a potential therapeutic vulnerability. However, disulfidptosis in pediatric AML (pAML) remains largely unexplored, with no comprehensive studies assessing its biological significance or clinical prognostic value.

Method: Here, we systematically characterize disulfidptosis in pediatric AML through multi-omics integration. Using ssGSEA, we quantified PDC patterns across bulk and single-cell transcriptomes, revealing distinct molecular subtypes via unsupervised clustering. Machine learning deciphered the biological networks underlying disulfidptosis, while in vitro experiments were performed to further validate.

Results: In this study, we demonstrated that elevated disulfidptosis scores were associated with poor prognosis and a hypermetabolic state. Notably, patients carrying different driver mutations exhibited distinct levels of disulfidptosis susceptibility. Through in vitro experiments utilizing both cell lines and primary patient-derived cells, we found that elevated expression of SLC7A11, a key regulator of disulfidptosis, correlated with chemoresistance. Furthermore, disulfidptosis signatures effectively stratified risk subgroups in pAML, revealing a novel subtype, DSP3, characterized by prominent disulfidptosis features, an immune-desert tumor microenvironment, and an unfavorable prognosis. Additionally, our in vitro experiments identified the GLUT1 inhibitor STF-31 and the mitochondrial-targeted agent darinaparsin as potential therapeutic options for DSP3 patients, and combining with conventional chemotherapy exhibited a synergistic anti-tumor effect.

Conclusion: In summary, this study employed multi-omics analysis to examine the characteristics of pAML in the context of disulfidptosis, identifying a novel disulfidptosis-related subtype, aiming to provide new insights for future studies on optimizing traditional regimen based on pAML pathogenesis.