Ferroptosis is an autophagic cell death process

• Published in: Cell research Vol. 26; no. 9; pp. 1021 - 1032
• Main Authors: Gao, Minghui, Monian, Prashant, Pan, Qiuhui, Zhang, Wei, Xiang, Jenny, Jiang, Xuejun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2016; Nature Publishing Group
• Subjects: 631/45/49; 631/80/82/39; Animals; Apoptosis - drug effects; Autophagy - drug effects; Biomedical and Life Sciences; Cell Biology; Cell death; Ferritins - metabolism; Ferroptosis; Genetic Testing; Homeostasis - drug effects; Humans; Iron; Iron - pharmacology; Life Sciences; Mice; Mortality; Nuclear Receptor Coactivators - metabolism; Original; original-article; Reactive Oxygen Species - metabolism; RNA Interference; ferritinophagy; ferroptosis; autophagy; iron homeostasis; reactive oxygen species
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2016.95

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 ferritino- phagy 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.