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Cited by 180Pancreatic function and diabetesFerroptosis and cancer prognosisCell death mechanisms and regulation

Ferroptosis-inducing agents compromise in vitro human islet viability and function

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Bruni, Antonio, Pepper, Andrew R., Pawlick, Rena L., Gala-Lopez, Boris, Gamble, Anissa F., Kin, Tatsuya, Seeberger, Karen, Korbutt, Gregory S. +3 more·2018·Cell Death & Disease
DOI 10.1038/s41419-018-0506-0PMC PMC5964226
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Abstract

Human islet transplantation has been hampered by donor cell death associated with the islet preparation procedure before transplantation. Regulated necrosis pathways are biochemically and morphologically distinct from apoptosis. Recently, ferroptosis was identified as a non-apoptotic form of iron-dependent regulated necrosis implicated in various pathological conditions. Mediators of islet oxidative stress, including glutathione peroxidase-4 (GPX4), have been identified as inhibitors of ferroptosis, and mechanisms that affect GPX4 function can impact islet function and viability. Ferroptosis has not been investigated directly in human islets, and its relevance in islet transplantation remains unknown. Herein, we sought to determine whether in vitro human islet viability and function is compromised in the presence of two distinct ferroptosis-inducing agents (FIA), erastin or RSL3, and whether these effects could be rescued with ferroptosis inhibitors, ferrostatin-1 (Fer-1), or desferrioxamine (DFO). Viability, as assessed by lactate dehydrogenase (LDH) release, revealed significant death in erastin- and RSL3-treated islets, 20.3% ± 3.8 and 24.4% ± 2.5, 24 h post culture, respectively. These effects were ameliorated in islets pre-treated with Fer-1 or the iron chelator, desferrioxamine (DFO). Stimulation index, a marker of islet function revealed a significant reduction in function in erastin-treated islets (control 1.97 ± 0.13 vs. 50 μM erastin 1.32 ± 0.1) (p < 0.05). Fer-1 and DFO pre-treatment alone did not augment islet viability or function. Pre-treatment of islets with erastin or Fer-1 did not impact in vivo engraftment in an immunodeficient mouse transplant model. Our data reveal that islets are indeed susceptible to ferroptosis in vitro, and induction of this novel cell death modality leads to compromised islet function, which can be recoverable in the presence of the ferroptosis inhibitors. The in vivo impact of this pathway in islet transplantation remains elusive given the constraints of our study, but warrants continued investigation.

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  • Deferoxamine has been reported to inhibit ferroptosis in several experimental disease models.

    “has been reported to inhibit ferroptosis in several experimental disease models (Ma et al., 2016; Bruni et al., 2018).”

    From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Bruni et al., 2018

    The Results section reports that deferoxamine (DFO) prevented erastin-induced ferroptotic cell death in cultured human islets. It does not establish DFO's effect in several experimental disease models: the Introduction attributes that broader finding to ferrostatins, not DFO. No page numbers are available in our copy. (LLM, conf=0.88)

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Authors
Bruni, A., Pepper, A. R., Pawlick, R. L., Gala-Lopez, B., Gamble, A. F., Kin, T., Seeberger, K., Korbutt, G. S., Bornstein, S. R., Linkermann, A., & Shapiro, A. M. J.
Affiliations
  • University of Alberta (CA)
  • University Hospital Carl Gustav Carus (DE)
Corresponding author
Shapiro, A. M. James
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2018-05-22
Volume
9
Issue
6
Pages
595-595
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-018-0506-0
PMC
PMC5964226
OpenAlex
W2803755660
Cited by
180
References
3
Citations by year
2026: 22 · 2025: 27 · 2024: 40 · 2023: 29 · 2022: 21 · 2021: 16 · 2020: 17 · 2019: 7 · 2018: 1
FWCI
10.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Government of Canada
  • Alberta Innovates - Health Solutions
  • Alberta Innovates
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
ferroptosis, human pancreatic islets, islet transplantation, erastin, RSL3, ferrostatin-1, deferoxamine, GPX4, islet viability, islet function, oxidative stress, iron chelation
MeSH terms
Insulin Secretion, Animals, Carbolines, Cells, Cultured, Cyclohexylamines, Deferoxamine, gamma-Glutamylcyclotransferase, Glucose, Humans, Iron, Islets of Langerhans, L-Lactate Dehydrogenase, Mice, Inbred C57BL, Phenylenediamines, Piperazines, RNA, Messenger, Tissue Survival, Apoptosis

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