Autophagy promotes ferroptosis by degradation of ferritin
Open accessAbstract
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.
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Ferroptosis is promoted by autophagic degradation of ferritin (ferritinophagy).
“ferroptosis, which is promoted by the autophagic degradation of ferritin (ferritinophagy) [573, 574]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [573]
Ferritin is selectively targeted for autophagic/lysosomal degradation by the cargo receptor NCOA4, a process required for liberating iron making it bioavailable.
“Ferritin is selectively targeted for autophagic/lysosomal degradation by the cargo receptor NCOA4 [53], a process required for liberating iron making it bioavailable to the cell [51], [53], [65].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [65]
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Self-citation
- Authors
- Hou, W., Xie, Y., Song, X., Sun, X., Lotze, M. T., Zeh, H. J., Kang, R., & Tang, D.
- Affiliations
- University of Pittsburgh (US)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- Corresponding author
- Tang, Daolin
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2016-06-24
- Volume
- 12
- Issue
- 8
- Pages
- 1425-1428
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC4968231
- OpenAlex
- W2414659015
- Cited by
- 2,332
- References
- 28
- Citations by year
- 2026: 278 · 2025: 361 · 2024: 383 · 2023: 412 · 2022: 320 · 2021: 265 · 2020: 145 · 2019: 85 · 2018: 45 · 2017: 29 · 2016: 7
- FWCI
- 49.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh (P30 CA047904)
- National Natural Science Foundation of China (201508020258, R01GM115366, 201400000004-4, RSG-16-014-01-CDD, P30CA047904, 201400000003, R01CA160417, 31171229, 201400000003-4, U1132005)
- Natural Science Foundation of Guangdong Province (31171229, RSG-16-014-01-CDD, 201400000003-4, R01CA160417, U1132005, P30CA047904, 201400000004-4, R01GM115366, 201508020258)
- National Institutes of Health (RSG-16-014-01-CDD)
- Cancer Institute, University of Pittsburgh (RSG-16-014-01-CDD, R01GM115366, R01CA160417, P30CA047904)
- National Cancer Institute (R01CA160417, R01CA181450, P30CA047904)
- National Institute of General Medical Sciences (R01GM115366)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- ferroptosis, ferritinophagy, ferritin degradation, NCOA4, ATG5, ATG7, lipid peroxidation, iron homeostasis, selective autophagy, regulated cell death, erastin
- MeSH terms
- Autophagy-Related Protein 5, Autophagy-Related Protein 7, Animals, Autophagy, Ferritins, Fibroblasts, Homeostasis, Humans, Iron, Pancreatic Neoplasms, Piperazines, Lipid Peroxidation, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Mice, Nuclear Receptor Coactivators
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