FDX1 Loss Drives AML Resistance to Copper-Induced Cell Death

Acute myeloid leukemia (AML) remains a formidable challenge in oncology, characterized by rapid disease progression and a five-year overall survival rate of approximately 10% for patients with relapsed or refractory disease. While targeted therapies such as venetoclax and FLT3 inhibitors have offered new avenues for treatment, the development of resistance and severe side effects continues to limit long-term outcomes. Recent research highlights a potential vulnerability in AML cells related to copper homeostasis, specifically through a unique form of cell death known as cuproptosis. A new study reveals that the downregulation of the mitochondrial protein FDX1 in AML patients promotes leukemic cell proliferation and confers resistance to this copper-dependent death pathway, suggesting a novel mechanism underlying treatment failure.

Copper is an essential trace element that serves as a cofactor for numerous enzymes involved in redox processes. However, excessive accumulation of copper can be toxic to cells. In AML, elevated serum copper levels have been strongly associated with inferior overall survival and reduced disease-free survival, indicating a complex relationship between copper dysregulation and disease prognosis. Cuproptosis is distinct from other well-characterized cell death mechanisms such as apoptosis or ferroptosis. It is mediated by mitochondrial proteotoxic stress, where copper directly binds to lipoylated proteins, leading to their oligomerization and subsequent cell death. Given that AML cells have a high dependence on mitochondrial respiration, they may possess an inherent vulnerability to cuproptosis induction, yet the specific molecular mechanisms that determine sensitivity or resistance in this context remained incompletely understood until now.

The study identified FDX1, a mitochondrial ferredoxin and key regulator of protein lipoylation, as the most significantly downregulated cuproptosis-related gene in AML patients compared to healthy controls. Clinical data from the cohort showed that serum copper concentrations were higher in AML patients than in normal controls, and these elevated levels correlated with poorer survival outcomes. Furthermore, immunohistochemical staining revealed reduced FDX1 protein expression in the bone marrow of primary AML patients. Lower FDX1 expression was independently associated with a worse prognosis, suggesting that the loss of this mitochondrial protein is a critical factor in the aggressive behavior of leukemia cells and their ability to evade copper-induced toxicity.

Functional experiments using AML cell lines demonstrated that FDX1 plays a pivotal role in controlling cell growth and sensitivity to copper. Overexpression of FDX1 significantly suppressed AML cell viability and induced cell cycle arrest in the G0/G1 phase, whereas knockdown of FDX1 markedly enhanced proliferation. In vivo studies using mouse models confirmed these findings, showing that mice harboring AML cells with overexpressed FDX1 exhibited reduced leukemia burden, longer survival, and less infiltration of leukemic cells into the bone marrow, liver, and spleen. Conversely, FDX1 deficiency promoted leukemic engraftment and disease progression, highlighting its tumor-suppressive function in the context of AML.

Mechanistically, the study elucidates how FDX1 modulates the cellular response to copper through the ROS/p53/ME1 signaling axis. FDX1 overexpression exacerbates mitochondrial damage, leading to the accumulation of reactive oxygen species (ROS). This ROS accumulation activates the p53 tumor suppressor pathway, which in turn transcriptionally represses the expression of malic enzyme 1 (ME1). The researchers confirmed that p53 directly binds to the promoter region of the ME1 gene, establishing a direct transcriptional link between mitochondrial stress and metabolic reprogramming. This pathway serves as a critical regulatory node that determines whether AML cells undergo cuproptosis or survive copper exposure.

ME1 is a cytosolic metabolic enzyme that catalyzes the decarboxylation of malate to pyruvate, playing a crucial role in maintaining mitochondrial NAD+/NADH homeostasis through the malate-aspartate shuttle. The study found that ME1 is highly expressed in AML patients and that higher ME1 levels are associated with poorer overall survival. Functionally, ME1 overexpression promoted AML cell viability and conferred resistance to cuproptosis. In contrast, the inhibition or knockdown of ME1 significantly enhanced the sensitivity of AML cells to copper-induced cell death. This suggests that ME1 acts as a metabolic shield that protects leukemia cells from the toxic effects of copper by maintaining redox balance and preventing the accumulation of lipoylated DLAT, a key trigger for cuproptosis.

The link between ME1 and cuproptosis resistance is mediated by the disruption of mitochondrial NAD+/NADH homeostasis. ME1 inhibition leads to a decrease in the mitochondrial NAD+/NADH ratio, which impairs the delipoylation of lipoylated DLAT. Since the delipoylation of DLAT is dependent on NAD+, the reduction in NAD+ levels caused by ME1 deficiency results in the accumulation of lipoylated DLAT. Under copper exposure, this accumulated lipoylated DLAT undergoes oligomerization, triggering the cuproptosis pathway. The researchers demonstrated that supplementing cells with pyruvate, a metabolite that supports NAD+ regeneration, could reverse the effects of ME1 inhibition, restoring cell viability and reducing DLAT oligomerization. This confirms that the metabolic disruption caused by ME1 loss is the primary driver of enhanced cuproptosis sensitivity.

To evaluate the therapeutic potential of targeting this axis, the study investigated the combination of a copper ionophore, elesclomol, with an ME1 inhibitor. In mouse models of AML, the combination therapy proved more effective than either agent alone. The combined treatment significantly reduced leukemia burden, prolonged survival, and alleviated symptoms such as splenomegaly and anemia. Importantly, blood biochemical analyses indicated that the combination did not cause significant hepatic or renal toxicity in the mice, suggesting a favorable safety profile. This synergistic effect arises because the ME1 inhibitor overcomes the resistance conferred by FDX1 downregulation, while the copper ionophore leverages the elevated copper levels inherent to AML to induce cell death.

These findings provide a comprehensive mechanistic framework for understanding cuproptosis resistance in AML. The downregulation of FDX1 in AML cells leads to reduced ROS production and p53 activation, resulting in the upregulation of ME1. This metabolic adaptation protects AML cells from copper-induced mitochondrial stress. By targeting ME1, it is possible to reverse this resistance and restore sensitivity to cuproptosis. The study underscores the importance of metabolic vulnerabilities in cancer therapy and highlights the potential of combining metabolic inhibitors with copper-based strategies to improve outcomes for AML patients. The identification of the FDX1-ROS-p53-ME1 axis offers a new perspective on how leukemia cells adapt to environmental stresses and survive treatment.

Despite these promising results, the study acknowledges several limitations. The broader applicability of ME1 inhibition in other cancers with copper dysregulation remains to be tested. Furthermore, pharmacokinetic and safety optimization of the combination therapy will be required before clinical translation. The study also notes that complete paired data for serum copper, FDX1, and ME1 expression along with survival information were not available for all patients, limiting the ability to construct a comprehensive prognostic model. Future prospective multicenter studies with complete matched clinical and molecular data are needed to validate the prognostic value and therapeutic relevance of the copper-FDX1-ME1 axis. Nevertheless, this research opens a new frontier in AML treatment by targeting the intersection of metal homeostasis and mitochondrial metabolism.

Subject of Research: Mechanisms of cuproptosis resistance in acute myeloid leukemia mediated by the FDX1/ROS/p53/ME1 axis

Article Title: FDX1 suppresses acute myeloid leukemia progression and reverses cuproptosis resistance via the ROS/p53/ME1 axis

Article References: Yao, L., Zhong, F., Bai, Q., Zeng, H., Qiu, Y., Yao, F., Xu, Y., Zhang, J., Lin, J., Deng, K., Huang, B., & Wang, X. (2026). FDX1 suppresses acute myeloid leukemia progression and reverses cuproptosis resistance via the ROS/p53/ME1 axis. iScience, 29(11), Article 117968. https://doi.org/10.1016/j.isci.2026.117968

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117968

Keywords: acute myeloid leukemia, cuproptosis, FDX1, ME1, p53 signaling, copper homeostasis, mitochondrial metabolism, cancer therapy, reactive oxygen species, DLAT oligomerization, suppresses, acute