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Publications

Journal Article Ppublish

PubMed: 40706290 DOI: 10.1016/j.redox.2025.103777

15-Lipoxygenase-dependent radiomitigation by NO ●-Donors suppresses ferroptosis in intestinal Epithelium: Multiomics MS imaging and LC-MS evidence.

Redox Biol 85:103777

Authors: Yulia Y Tyurina, Hua Tian, Haider H Dar, Mert Akdogan, Ecem Saritas, Vladimir A Tyurin, Louis J Sparvero, Alexander A Kapralov, Galina Shurin, Renee Fisher, Michael W Epperly, Kunal Singh, Yuri L Bunimovich, Joel S Greenberger, Valerian E Kagan, Hülya Bayir

Affiliations

  • Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, PA, 15219, USA.
  • Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
  • Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
  • Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, PA, 15219, USA; Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
  • Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.

Abstract

Threats of irradiation (IR) exposure increase the need for radiomitigators. An important contributor to radiation injury is ferroptosis, triggered by the disbalanced redox metabolism. We showed that 15-lipoxygenase (15-LOX) catalyzed peroxidation of arachidonoyl-phosphatidyl-ethanolamine is an essential ferroptotic response of ileum to total body IR (TBI). Given that nitric oxide (NO ● ) can suppress ferroptosis by inhibiting 15-LOX and by directly scavenging lipid radicals, we tested NO ●-donors with optimized half decay times as radiomitigators. Here, we report that diethylenetriamine-NONOate (DETA-NONOate) (with a half decay-time of 20 hr) acted as an effective radiomitigator when administered 24 hr after exposure to TBI (9.25Gy) and markedly prolonged survival of C57BlJ6 mice by - i) decreasing the levels of pro-ferroptotic HOO-PUFA-PE signals, and ii) decreasing the expression of 15-LOX2 - in the ileum on day 4 after TBI. Redox lipidomics LC-MS and two mass spectrometric imaging (MSI) protocols: i) single-cell multi-omics Dual C 60/gas cluster ion beam (GCIB) secondary ion mass spectrometry (SIMS), and ii) matrix-assisted laser desorption ionization (MALDI)-MSI, visualized DETA-NONOate's effectiveness in suppressing TBI-induced HOO-PUFA-PE production and preserving intestinal epithelium structural integrity. In vitro, NO ● donors were effective in suppressing PUFA-PE peroxidation and ferroptotic death in human intestinal epithelial cells (FHs 74 Int) exposed to radiation (8Gy) plus enzymatic (15-LOX2) pro-ferroptotic stimulation.

MeSH

Cells, Lipoxygenase, Ferroptosis, Ileum, Arachidonate 15-Lipoxygenase, Epithelium