# Selective Inhibitors of Pro-Ferroptotic Lipoxygenases - Next Generation Radiomitigators

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $534,477

## Abstract

In spite of the serious threats of intentional or accidental exposures to radiation, molecular mechanisms of injury after
total body irradiation (TBI) are not completely clear, hence radiomitigative approaches remain insufficient. Our
discoveries of oxygenated cardiolipins (CLs) as required stages of TBI apoptosis have already resulted in
mitochondria-targeted GS-nitroxides and imidazole-substituted fatty acids as anti-apoptotic radiomitigators. Similarly,
deciphering the TBI ferroptotic signaling by hydroperoxy-phosphatidylethanolamines (HOO-PEs) produced by 15-
lipoxygenases (15LOX) complexes with phosphatidylethanolamine-binding protein 1 (15-LOX/PEBP1) guides us to
new inhibitors as novel radiomitigators. Our demonstration of “theft- ferroptosis” by a bacterial pathogen,
Pseudomonas aeruginosa, utilizing its 15-LOX (pLoxA) (12) to trigger ferroptosis of the host (epithelial) cells indicates
that TBI induced non-sterile inflammation may be also therapeutically targeted. Our central hypothesis is that radiation
triggered responses engage several types of programmed necrotic death, particularly ferroptosis, in GI epithelial cells
and the major innate immune cells, neutrophils and macrophages, evolving over time and driving necro-inflammatory
vs pro-resolving apoptotic responses during sterile and non-sterile inflammation and culminating in multiple organ
dysfunction and mortality. This sets the stage for a principally new understanding of the TBI mechanisms and leads to
a new harmonized radiomitigation strategy of time- and mechanism-specific targeting of the leading cell death
pathways. Our hypothesis will be tested as follows: Aim 1: By employing Redox Lipidomics identify specific
oxygenated phospholipid signatures of the major death programs in epithelial cells, neutrophils and macrophages of
the GI of irradiated mice at different stages of sterile and non-sterile necro-inflammation. These newly discovered TBI
lipid biomarkers will be related to: i) specific protein markers of cell death, ii) major pro- and anti-inflammatory lipid
mediators, iii) cytokines, and iv) breach of the epithelial barrier and immunosuppression. Aim 2: Explore molecular
mechanisms of sensitivity/resistance to ferroptosis of macrophages and neutrophils polarized to M1 (N1) and M2 (N2)
states in response to pro-/anti-inflammatory conditions and expression of 15LOX and iNOS/NO• system in vitro and
TBI induced ferroptosis in vivo. We will employ 15LOX and iNOS KO mice and also quantitatively assess the role of
P. aeruginosa and its pLoxA in gut ferroptosis and radiosensitivity of mice to TBI. Aim 3: Design new selective
inhibitors of pro-ferroptotic catalytic activity of mammalian 15LOX as well as prokaryotic pLoxA of P. aeruginosa and
test them as anti-ferroptotic radiomitigators during sterile and non-sterile stages of TBI radiation disease. Overall, this
project is based on an entirely new concept that abandons the search for a single “silver-bullet” radiomitigator and...

## Key facts

- **NIH application ID:** 10176413
- **Project number:** 5U01AI156924-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Valerian E Kagan
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $534,477
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176413

## Citation

> US National Institutes of Health, RePORTER application 10176413, Selective Inhibitors of Pro-Ferroptotic Lipoxygenases - Next Generation Radiomitigators (5U01AI156924-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10176413. Licensed CC0.

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