title: Ferroptosis is an autophagic cell death process.
abstract: Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis.
authors: Department of Clinical Laboratory, Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.|Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Minghui
authors: M
authors: Gao
authors: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Prashant
authors: P
authors: Monian
authors: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.|Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Qiuhui
authors: Q
authors: Pan
authors: Genomics Resources Core Facility, Weill Cornell Medical College, New York, USA.
authors: Wei
authors: W
authors: Zhang
authors: Genomics Resources Core Facility, Weill Cornell Medical College, New York, USA.
authors: Jenny
authors: J
authors: Xiang
authors: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Xuejun
authors: X
authors: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D005293:Ferritins / Q000378:metabolism; D005820:Genetic Testing; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D051379:Mice; D056918:Nuclear Receptor Coactivators / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C111382:NCOA4 protein, human; C508724:NcoA4 protein, mouse; D056918:Nuclear Receptor Coactivators; D017382:Reactive Oxygen Species; D005293:Ferritins; D007501:Iron