This study identifies multiple molecular components and mechanisms of ferroptosis, a form of regulated necrosis. The authors found that nutrient starvation, particularly amino acid deprivation, can induce a potent and rapid necrosis process in a serum-dependent manner. Two key serum factors, transferrin and the amino acid glutamine, were identified as inducers of ferroptosis. The cell surface transferrin receptor and the intracellular metabolic pathway of glutaminolysis were found to play crucial roles in this process. Inhibition of glutaminolysis, a critical component of ferroptosis, reduced heart injury caused by ischemia-reperfusion, suggesting a potential therapeutic approach for related diseases. The study also highlights the importance of glutathione depletion and iron availability in the induction of ferroptosis, providing insights into the molecular mechanisms underlying this form of programmed cell death.This study identifies multiple molecular components and mechanisms of ferroptosis, a form of regulated necrosis. The authors found that nutrient starvation, particularly amino acid deprivation, can induce a potent and rapid necrosis process in a serum-dependent manner. Two key serum factors, transferrin and the amino acid glutamine, were identified as inducers of ferroptosis. The cell surface transferrin receptor and the intracellular metabolic pathway of glutaminolysis were found to play crucial roles in this process. Inhibition of glutaminolysis, a critical component of ferroptosis, reduced heart injury caused by ischemia-reperfusion, suggesting a potential therapeutic approach for related diseases. The study also highlights the importance of glutathione depletion and iron availability in the induction of ferroptosis, providing insights into the molecular mechanisms underlying this form of programmed cell death.