Ferroptosis is an iron-dependent form of regulated necrosis, characterized by the accumulation of reactive oxygen species (ROS) and lipid peroxides. It plays a role in various human diseases, including ischemic organ damage and cancer. This study demonstrates that ferroptosis is an autophagic cell death process, with autophagy promoting ferroptosis through a specific form of autophagy called ferritinophagy. Ferritinophagy involves the degradation of ferritin, an iron storage protein, by the cargo receptor NCOA4, leading to the release of labile iron and subsequent ROS accumulation, which drives ferroptotic cell death. The study identifies multiple autophagy-related genes as positive regulators of ferroptosis, and shows that inhibition of autophagy or NCOA4 prevents ferroptosis by reducing labile iron and ROS levels. The findings highlight the critical role of autophagy in maintaining cellular iron homeostasis and its involvement in ferroptosis. The study also shows that autophagy is required for ferroptosis-associated ROS and lipid ROS accumulation, and that autophagy inhibition can significantly attenuate ferroptosis. These results suggest that ferroptosis is a form of autophagic cell death, and that NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis. The study provides important insights into the mechanisms of ferroptosis and its potential therapeutic implications in cancer treatment.Ferroptosis is an iron-dependent form of regulated necrosis, characterized by the accumulation of reactive oxygen species (ROS) and lipid peroxides. It plays a role in various human diseases, including ischemic organ damage and cancer. This study demonstrates that ferroptosis is an autophagic cell death process, with autophagy promoting ferroptosis through a specific form of autophagy called ferritinophagy. Ferritinophagy involves the degradation of ferritin, an iron storage protein, by the cargo receptor NCOA4, leading to the release of labile iron and subsequent ROS accumulation, which drives ferroptotic cell death. The study identifies multiple autophagy-related genes as positive regulators of ferroptosis, and shows that inhibition of autophagy or NCOA4 prevents ferroptosis by reducing labile iron and ROS levels. The findings highlight the critical role of autophagy in maintaining cellular iron homeostasis and its involvement in ferroptosis. The study also shows that autophagy is required for ferroptosis-associated ROS and lipid ROS accumulation, and that autophagy inhibition can significantly attenuate ferroptosis. These results suggest that ferroptosis is a form of autophagic cell death, and that NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis. The study provides important insights into the mechanisms of ferroptosis and its potential therapeutic implications in cancer treatment.