Ferroptosis is a newly identified form of regulated necrosis linked to various human diseases. This study reveals key molecular components and the interplay between ferroptosis and cellular metabolism. Nutrient deprivation, particularly amino acid starvation, triggers a more rapid and potent necrotic process, which is identified as ferroptosis. Two serum factors, transferrin and glutamine, are shown to induce ferroptosis. The transferrin receptor and glutaminolysis, a metabolic pathway fueled by glutamine, are essential for this process. Inhibiting glutaminolysis reduces heart injury caused by ischemia-reperfusion, suggesting its potential as a therapeutic target. Transferrin, an iron-carrying protein, is required for ferroptosis, as is glutamine, which is metabolized through glutaminolysis. The study demonstrates that ferroptosis requires cystine starvation and depletion of cellular glutathione, and that it is a form of iron-dependent cell death. Inhibiting glutaminolysis prevents ischemia-reperfusion injury in an ex vivo heart model, highlighting its therapeutic potential. The findings underscore the importance of glutaminolysis and transferrin in ferroptosis and suggest that targeting these pathways could be beneficial for treating diseases associated with ferroptosis.Ferroptosis is a newly identified form of regulated necrosis linked to various human diseases. This study reveals key molecular components and the interplay between ferroptosis and cellular metabolism. Nutrient deprivation, particularly amino acid starvation, triggers a more rapid and potent necrotic process, which is identified as ferroptosis. Two serum factors, transferrin and glutamine, are shown to induce ferroptosis. The transferrin receptor and glutaminolysis, a metabolic pathway fueled by glutamine, are essential for this process. Inhibiting glutaminolysis reduces heart injury caused by ischemia-reperfusion, suggesting its potential as a therapeutic target. Transferrin, an iron-carrying protein, is required for ferroptosis, as is glutamine, which is metabolized through glutaminolysis. The study demonstrates that ferroptosis requires cystine starvation and depletion of cellular glutathione, and that it is a form of iron-dependent cell death. Inhibiting glutaminolysis prevents ischemia-reperfusion injury in an ex vivo heart model, highlighting its therapeutic potential. The findings underscore the importance of glutaminolysis and transferrin in ferroptosis and suggest that targeting these pathways could be beneficial for treating diseases associated with ferroptosis.