TY - JOUR
T1 - 15-LOX-catalytic bias towards ether-(alkenyl)-ETE-PEs oxidation bestows selectivity of PRO-ferroptotic cell death signaling
AU - Tyurina, Yulia Y.
AU - Mikulska-Ruminska, Karolina
AU - Tyurin, Vladimir A.
AU - Kleiboeker, Brian A.
AU - Kapralov, Alexander A.
AU - Hashimoto, Ayumi
AU - Sparvero, Louis J.
AU - Dar, Haider H.
AU - Akdogan, Mert
AU - Yamada, Kazuhiro
AU - Zhao, Jinming
AU - Kelestemur, Taha
AU - Saritas, Ecem
AU - Samovich, Sviatlana N.
AU - Holman, Theodore R.
AU - Bunimovich, Yuri L.
AU - Nefedova, Yulia
AU - Gabrilovich, Dmitry I.
AU - Wenzel, Sally E.
AU - Bahar, Ivet
AU - Kagan, Valerian E.
AU - Bayır, Hülya
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/12
Y1 - 2026/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105042239839
U2 - 10.1038/s41467-026-71869-z
DO - 10.1038/s41467-026-71869-z
M3 - Article
C2 - 42310294
AN - SCOPUS:105042239839
SN - 2041-1723
VL - 17
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5360
ER -