15-LOX-catalytic bias towards ether-(alkenyl)-ETE-PEs oxidation bestows selectivity of PRO-ferroptotic cell death signaling
Ether (alkyl/alkenyl) phospholipids, particularly phosphatidylethanolamine (PE) and phosphatidylcholine (PC), are broadly represented in membranes, but their physiological functions are poorly characterized. The antioxidant role of plasmalogens realized via oxidation of sn-1 vinyl bond has been associated with anti-ferroptotic regulatory function. Alternatively, peroxidation of polyunsaturated fatty acid (PUFA) in sn-2-position of alkenyl-PEs can be pro-ferroptotic. Since 15-LOXs generate 15-HpETE-PEs as ferroptotic signals, we explored alkyl/alkenyl-ETE-PE as substrates of enzymatic peroxidation. Using redox lipidomics, biochemical, biophysical, genetic approaches, and molecular dynamics simulations, we established that both isoforms of 15-LOX (15-LOX-1 and 15-LOX-2) selectively oxidize alkyl/alkenyl-ETE-PE (but not alkyl/alkenyl-ETE-PC), forming 15-HpETE-PEs, triggering ferroptotic death, independently of the vinyl bond. We showed that LOX-catalyzed peroxidation rate of sn-1 vinyl bond is ~500-fold lower than sn-2-ETE-PE, thus excluding the antioxidant role of plasmalogens in ferroptosis. We showed 15-LOX-driven production of sn-1-alkenyl-sn-2-15-HpETE-PE acts as pathogenic factor in acute/chronic diseases: asthma, cancer, brain trauma, skin UVB-injury. Thus, 15-LOX-catalyzed bias towards oxidation of alkenyl-ETE-PE may represent a new therapeutic target.
Authors
- Kazuhiro Yamada (ORCID: https://orcid.org/0000-0001-6460-8312)
- Yulia Nefedova (ORCID: https://orcid.org/0000-0002-5121-9294)
- Louis J. Sparvero (ORCID: https://orcid.org/0000-0001-6347-8448)
- Taha Keleştemur (ORCID: https://orcid.org/0000-0003-3616-1204)
- Yuri L. Bunimovich (ORCID: https://orcid.org/0000-0002-7920-8781)
- Ayumi Hashimoto (ORCID: https://orcid.org/0000-0002-6655-4896)
- Karolina Mikulska‐Ruminska (ORCID: https://orcid.org/0000-0001-7227-5503)
- Vladimir A. Tyurin (ORCID: https://orcid.org/0000-0002-3474-1697)
- Dmitry I. Gabrilovich (ORCID: https://orcid.org/0000-0001-9913-6407)
- Alexandr A. Kapralov (ORCID: https://orcid.org/0000-0002-3006-916X)
- Valerian E. Kagan (ORCID: https://orcid.org/0000-0002-7245-1885)
- Haider H. Dar (ORCID: https://orcid.org/0000-0001-9586-7288)
- Yulia Y. Tyurina (ORCID: https://orcid.org/0000-0003-0287-2091)
- Hülya Bayır (ORCID: https://orcid.org/0000-0003-2361-4120)
- Sally E. Wenzel (ORCID: https://orcid.org/0000-0002-4242-0164)
- İvet Bahar (ORCID: https://orcid.org/0000-0001-9959-4176)
- Brian Kleiboeker (ORCID: https://orcid.org/0000-0002-3196-1803)
- Theodore R. Holman (ORCID: https://orcid.org/0000-0001-8072-2959)
- Jinming Zhao (ORCID: https://orcid.org/0000-0003-4700-9734)
- Mert Akdogan
- Ecem Saritas
- Sviatlana N. Samovich
Institutions
- The Wistar Institute (US)
- University of Pittsburgh (US)
- University of California, Santa Cruz (US)
- Columbia University Irving Medical Center (US)
- Nicolaus Copernicus University (PL)
- Institute of Physics (PL)
- Stony Brook School (US)
- AstraZeneca (Netherlands) (NL)
- Osaka Metropolitan University (JP)
- Stony Brook University (US)
- Tokyo Metropolitan University (JP)
- Columbia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-17
- DOI
- https://doi.org/10.1038/s41467-026-71869-z
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Narodowe Centrum Nauki
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke