Tocotrienols exhibit superior ferroptosis inhibition over tocopherols.

Ferroptosis is a regulated form of cell death characterized by iron-dependent phospholipid peroxidation. Micronutrients play a critical role in modulating cellular sensitivity to ferroptosis, with vitamin E being a well-known ferroptosis inhibitor through its lipophilic antioxidant property. While vitamin E naturally exists in two forms of tocochromanols, namely tocopherols and tocotrienols, each comprising α, β, γ, and δ analogs with distinct antioxidant capacities and metabolic profiles, only α-tocopherol has been the focus of most ferroptosis studies. Here, we compared the efficacy of all vitamin E analogs, including tocopherols, tocotrienols and Trolox, in terms of their ability to prevent ferroptosis and their antioxidant activities linked to suppressing lipid peroxidation. We demonstrate that tocotrienols exhibit superior ferroptosis inhibition over tocopherols. Tocotrienols prevented ferroptosis induced by both pharmacological models (inhibition of GPX4, xCT or glutathione synthesis) and a genetic model of inducible Gpx4 knockout at significantly lower concentrations than tocopherols (e.g., EC50 of 0.12 μM for α-tocotrienol and 2.0 μM for α-tocopherol in Gpx4 knockout cells). Consistent with this, tocotrienols exhibited greater antioxidant activities in suppressing lipid peroxidation. These findings highlight the distinct properties of vitamin E analogs in regulating ferroptosis and underscore the superior potential of tocotrienols as potent ferroptosis suppressors.