Increased response to metformin was associated with disrupted lipid metabolism and ferroptosis, with FLT3-ITD and IDH1/2 mutant AMLs showing the highest enrichment scores for these signatures. Extracellular flux analysis showed that metformin treatment completely abolished mitochondrial metabolism and promotedglycolysis in wild-type samples, whereas FLT3 and IDH1/2 mutants appeared to be less efficient in rewiring their metabolism upon OXPHOS inhibition. To better understand the association between metformin and ferroptosis, we focused on lipid peroxidation, reactive oxygen species (ROS) formation, iron metabolism and lipid composition. Metformin treatment increased both lipid peroxidation and ROS levels, especially in FLT3and IDH1/2 mutant samples. As iron is an essential co-factor in ferroptosis, combining metformin with an iron quelator led to a strong antagonistic effect. Metabolome analysis revealed an imbalance in the lipid pool, with higher poly-unsaturated fatty acids in this subset of mutant patients, increasing their susceptibility to lipid peroxidation at baseline. Since these samples also showed increased expression of CD36, an important fatty acid transporter, we disrupted lipid dynamics to evaluate the consequences for metformin treatment. Co-treatment with palmitate, a saturated fatty acid, increased metformin sensitivity, and CD36 knockdown rendered IDH2^R140Q cells more resistant. Finally, combination with a DGAT1 inhibitor, an enzyme involved in lipid droplet formation, showed additive-to-synergistic effects in cell lines and primary samples, emphasizing the importance of lipid homeostasis for metformin sensitivity.