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DNA methyltransferase inhibitors (DNMTis), such as decitabine, are widely used to treat myelodysplastic syndromes and acute myeloid leukemia (AML), particularly in elderly patients due to their low-dose regimens. However, drug resistance often emerges, emphasizing the need for deeper insights into resistance mechanisms and new therapeutic strategies. We show that, while DAC induces DNMT1 depletion, and profound mitochondrial dysfunction-resulting in apoptosis in a subset of cells-a majority demonstrates remarkable adaptation, persisting via rewired metabolic and proteostatic pathways. Integration of transcriptomic and metabolomic reveals that upregulation and sustained stabilization of protein ANPEP, a glutamate-glutathione metabolic axis regulator, is critical for counteracting DAC-induced oxidative stress and facilitating cell survival. Inhibition or targeted knockdown of ANPEP potentiates DAC efficacy even in DAC-Venetoclax resistant AML cell lines. The stabilization of ANPEP is governed post-translationally, likely via loss of E3 ligase or induction of deubiquitinase activity and is likely linked to DAC-driven chromatin remodeling. Functional disruption of ANPEP significantly enhances mitochondrial ROS and apoptosis in AML cells, particularly in combination with DAC. Additionally, physical association between DNMT1 and the H3K9me2 writer EHMT1 is hypothesized to contribute to chromatin silencing, with DAC-induced alterations fostering durable changes in chromatin structure and metabolic gene accessibility. Collectively, these findings elucidate a multi-layered adaptation network underpinning AML resistance to epigenetic therapy and highlight the therapeutic potential of dual targeting metabolic and epigenetic resilience mechanisms to improve outcomes in AML.