Autophagy promotes ferroptosis by degradation of ferritin

Autophagy. 2016 Aug 2;12(8):1425-8. doi: 10.1080/15548627.2016.1187366. Epub 2016 May 31.


Macroautophagy/autophagy is an evolutionarily conserved degradation pathway that maintains homeostasis. Ferroptosis, a novel form of regulated cell death, is characterized by a production of reactive oxygen species from accumulated iron and lipid peroxidation. However, the relationship between autophagy and ferroptosis at the genetic level remains unclear. Here, we demonstrated that autophagy contributes to ferroptosis by degradation of ferritin in fibroblasts and cancer cells. Knockout or knockdown of Atg5 (autophagy-related 5) and Atg7 limited erastin-induced ferroptosis with decreased intracellular ferrous iron levels, and lipid peroxidation. Remarkably, NCOA4 (nuclear receptor coactivator 4) was a selective cargo receptor for the selective autophagic turnover of ferritin (namely ferritinophagy) in ferroptosis. Consistently, genetic inhibition of NCOA4 inhibited ferritin degradation and suppressed ferroptosis. In contrast, overexpression of NCOA4 increased ferritin degradation and promoted ferroptosis. These findings provide novel insight into the interplay between autophagy and regulated cell death.

Keywords: NCOA4; autophagy; ferritin; ferritinophagy; ferroptosis; iron; lipid; pancreatic cancer.

MeSH terms

  • Animals
  • Apoptosis
  • Autophagy
  • Autophagy-Related Protein 5 / metabolism
  • Autophagy-Related Protein 7 / metabolism*
  • Ferritins / chemistry*
  • Fibroblasts / metabolism
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Lipid Peroxidation*
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Coactivators / metabolism*
  • Pancreatic Neoplasms / metabolism*
  • Piperazines / metabolism
  • Reactive Oxygen Species / metabolism*


  • ATG5 protein, human
  • Atg5 protein, mouse
  • Atg7 protein, mouse
  • Autophagy-Related Protein 5
  • NCOA4 protein, human
  • NcoA4 protein, mouse
  • Nuclear Receptor Coactivators
  • Piperazines
  • Reactive Oxygen Species
  • erastin
  • Ferritins
  • Iron
  • ATG7 protein, human
  • Autophagy-Related Protein 7