Context-dependent regulation of ferroptosis sensitivity

Leslie Magtanong, Grace D. Mueller, Kevin J. Williams, Maximilian Billmann, Katherine Chan, David A. Armenta, Lauren E. Pope, Jason Moffat, Charles Boone, Chad L. Myers, James A. Olzmann, Steven J. Bensinger, Scott J. Dixon

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Ferroptosis is an important mediator of pathophysiological cell death and an emerging target for cancer therapy. Whether ferroptosis sensitivity is governed by a single regulatory mechanism is unclear. Here, based on the integration of 24 published chemical genetic screens combined with targeted follow-up experimentation, we find that the genetic regulation of ferroptosis sensitivity is highly variable and context-dependent. For example, the lipid metabolic gene acyl-coenzyme A (CoA) synthetase long chain family member 4 (ACSL4) appears far more essential for ferroptosis triggered by direct inhibition of the lipid hydroperoxidase glutathione peroxidase 4 (GPX4) than by cystine deprivation. Despite this, distinct pro-ferroptotic stimuli converge upon a common lethal effector mechanism: accumulation of lipid peroxides at the plasma membrane. These results indicate that distinct genetic mechanisms regulate ferroptosis sensitivity, with implications for the initiation and analysis of this process in vivo.

Original languageEnglish (US)
Pages (from-to)1409-1418.e6
JournalCell Chemical Biology
Volume29
Issue number9
DOIs
StatePublished - Sep 15 2022

Bibliographical note

Funding Information:
We thank T. Stearns, K. Aulakh, R. Clime, A. Habsid, A. Tong, and M. Costanzo for help with experiments and K. Woerpel, R. Skouta, and H. Xiao for reagents. M.B. and C.L.M. were partially supported by the National Science Foundation ( 1818293 ). J.M. and C.B. were supported by a Genome Canada DIG Phase 2 award. J.M. is a Canada Research Chair Tier 2 in Functional Genomics of Cancer, and C.B. holds a Canada Research Chair Tier 1 in Functional Genomics and Proteomics, is a fellow of the Canadian Institute for Advanced Research (CIFAR), and was supported by the Canadian Institutes of Health Research ( PJT-180285 ). This work was also supported by awards from the National Institutes of Health to C.L.M. ( R01HG005084 and R01HG005853 ), J.A.O. ( R01GM112948 ), S.J.B. ( HL146358 ), and S.J.D. ( R01GM122923 ).

Funding Information:
We thank T. Stearns, K. Aulakh, R. Clime, A. Habsid, A. Tong, and M. Costanzo for help with experiments and K. Woerpel, R. Skouta, and H. Xiao for reagents. M.B. and C.L.M. were partially supported by the National Science Foundation (1818293). J.M. and C.B. were supported by a Genome Canada DIG Phase 2 award. J.M. is a Canada Research Chair Tier 2 in Functional Genomics of Cancer, and C.B. holds a Canada Research Chair Tier 1 in Functional Genomics and Proteomics, is a fellow of the Canadian Institute for Advanced Research (CIFAR), and was supported by the Canadian Institutes of Health Research (PJT-180285). This work was also supported by awards from the National Institutes of Health to C.L.M. (R01HG005084 and R01HG005853), J.A.O. (R01GM112948), S.J.B. (HL146358), and S.J.D. (R01GM122923). Conceptualization, L.M. and S.J.D.; methodology, L.M. G.D.M. K.J.W. and J.A.O.; investigation, L.M. G.D.M. K.J.W. M.B. K.C. and D.A.A.; Data curation, L.M. G.D.M. L.E.P.; writing – original draft, L.M. and S.J.D.; writing – review & editing, L.M. G.D.M. K.J.W. J.A.O. S.J.B. and S.J.D.; supervision, J.M. C.B. C.M. J.A.O. S.J.B. and S.J.D. J.A.O. is a member of the scientific advisory board of Vicinitas Therapeutics. S.J.D. is a co-founder of Prothegen and a member of the scientific advisory boards for Ferro Therapeutics and Hillstream BioPharma. J.A.O. and S.J.D. hold patents related to ferroptosis.

Publisher Copyright:
© 2022 Elsevier Ltd

Keywords

  • ACSL4
  • cancer
  • ether lipid
  • ferroptosis
  • iron
  • PUFA
  • ROS

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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