Ferroptosis is an iron-dependent form of regulated necrosis that plays a critical role in various human diseases, including ischemic organ damage and cancer. This study reveals that autophagy, particularly a form of autophagy called ferritinophagy, is essential for ferroptosis. Using RNAi screening and genetic analysis, the researchers identified multiple autophagy-related genes that positively regulate ferroptosis. Ferroptosis induction leads to autophagy activation, resulting in the degradation of ferritin and the cargo receptor NCOA4. Inhibition of ferritinophagy by blocking autophagy or knocking down NCOA4 prevents the accumulation of ferroptosis-associated labile iron and reactive oxygen species (ROS), as well as ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis. The study also demonstrates that autophagy is a positive regulator of ferroptosis, with autophagy inhibitors like BafA1 and chloroquine significantly blocking erastin-induced ferroptosis. Additionally, autophagy is required for the accumulation of ROS and lipid ROS during ferroptosis, which are essential for the process. The findings suggest that autophagy plays a crucial role in regulating cellular iron homeostasis and ROS generation, which are key factors in ferroptosis. The study highlights the importance of autophagy in ferroptosis and raises concerns about the use of autophagy inhibitors in cancer treatment, as some drugs like sorafenib may induce ferroptotic cell death. Overall, this study provides new insights into the mechanisms of ferroptosis and its regulation by autophagy.Ferroptosis is an iron-dependent form of regulated necrosis that plays a critical role in various human diseases, including ischemic organ damage and cancer. This study reveals that autophagy, particularly a form of autophagy called ferritinophagy, is essential for ferroptosis. Using RNAi screening and genetic analysis, the researchers identified multiple autophagy-related genes that positively regulate ferroptosis. Ferroptosis induction leads to autophagy activation, resulting in the degradation of ferritin and the cargo receptor NCOA4. Inhibition of ferritinophagy by blocking autophagy or knocking down NCOA4 prevents the accumulation of ferroptosis-associated labile iron and reactive oxygen species (ROS), as well as ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis. The study also demonstrates that autophagy is a positive regulator of ferroptosis, with autophagy inhibitors like BafA1 and chloroquine significantly blocking erastin-induced ferroptosis. Additionally, autophagy is required for the accumulation of ROS and lipid ROS during ferroptosis, which are essential for the process. The findings suggest that autophagy plays a crucial role in regulating cellular iron homeostasis and ROS generation, which are key factors in ferroptosis. The study highlights the importance of autophagy in ferroptosis and raises concerns about the use of autophagy inhibitors in cancer treatment, as some drugs like sorafenib may induce ferroptotic cell death. Overall, this study provides new insights into the mechanisms of ferroptosis and its regulation by autophagy.