Identification of essential sites of lipid peroxidation in ferroptosis

A. Nikolai von Krusenstiern, Ryan N. Robson, Naixin Qian, Baiyu Qiu, Fanghao Hu, Eduard Reznik, Nailah Smith, Fereshteh Zandkarimi, Verna M. Estes, Marcel Dupont, Tal Hirschhorn, Mikhail S. Shchepinov, Wei Min, K. A. Woerpel, Brent R. Stockwell

Research output: Contribution to journalArticlepeer-review


Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure–activity–distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)719-730
Number of pages12
JournalNature Chemical Biology
Issue number6
StatePublished - Jun 2023

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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