Radiation countermeasure gamma-tocotrienol inhibits accumulation of lipid peroxidation products in the serum of nonhuman primates exposed to partial- or total-body radiation – A hallmark of inhibition of irradiation-induced ferroptosis?

Gamma-tocotrienol (GT3) is one of the constituents of vitamin E that
demonstrated significant radioprotective efficacy in murine and nonhuman
primate (NHP) models. Considering the antioxidant activity of GT3 and its
role in terminating lipid peroxidation, we hypothesize that mechanism of
radioprotective effect of GT3 may involve the inhibition of
irradiation-induced ferroptosis – a form of regulated cell death
characterized by excessive, iron-dependent, peroxidation of lipids in
cellular membranes. To test this hypothesis, the metabolomic and proteomic
data from serum samples of GT3- or vehicle-treated NHPs exposed to 12 Gy
(partial- or total-body) radiation were analyzed with focus on lipid
peroxidation markers and proteins involved in iron metabolism. Four
secondary lipid peroxidation products were identified, including
4-oxo-2-nonenal (4-ONE), 4-hydroperoxy-2-nonenal (4-HPNE),
3,4-epoxynonanal (3,4-ENA), and trans-4,5-epoxy-(2E)-decenal (4,5-EDE). In
vehicle-treated animals, their concentrations increased significantly as
soon as 4 h after irradiation and then gradually declined. GT3 treatment
mitigated this radiation-induced increase. In addition to lipid
peroxidation products, similar patterns of change were observed for
several polyunsaturated, monounsaturated, and saturated fatty acids as
well as amino acids such as lysine and its derivatives. Taken together,
these metabolomic changes suggest that irradiation induces cellular
membrane damage through enhanced lipid peroxidation, while GT3 exerts a
protective effect against this process. In addition, GT3 increased serum
levels of haptoglobin and hemopexin—two plasma scavenger proteins that
play complementary protective roles in iron and heme homeostasis. Although
the present study does not conclusively demonstrate that GT3 mediates
radioprotection via inhibition of ferroptosis, the data suggest that GT3
limits membrane damage and reduces susceptibility to ferroptosis by
enhancing iron and heme scavenging. Further investigation into the
interaction between GT3 and key components of ferroptosis following
exposure to ionizing radiation is therefore warranted.