Regulation of lipid oxidation and ferroptosis by a tunable axis of vitamin E, high-density lipoprotein, and scavenger...

Ferroptosis is caused by lethal peroxidative damage to cell membrane phospholipids (PL) containing polyunsaturated fatty acid (PUFA) tail groups. Mechanisms to control cell membrane PL oxidation and ferroptosis include cellular expression of glutathione peroxidase 4 (GPx4), which repairs oxidized cell membrane PL, and the lipophilic antioxidant alpha-tocopherol (α-toc), an active form of Vitamin E. Data show that α-toc can rescue cells from ferroptosis in vitro and in vivo even in the absence of GPx4. Yet, pathways by which α-toc is transported in blood, for instance in high- and low-density lipoproteins (HDL and LDL), for delivery to target cells to prevent PL oxidation and ferroptosis are unknown. We hypothesized that HDLs specifically target delivery of α-toc to the cell membrane to regulate PL oxidation and sensitivity to ferroptosis. We employed native lipoproteins and synthetic HDL-like nanoparticles made using either organic or gold nanoparticle cores (ocHDL NP or Au-HDL NP, respectively). The bottom-up synthesis strategies enabled control over the physicochemical properties of HDL NP, including α-toc content. Using cancer and neuronal cell models, our data show native HDLs and synthetic HDL NPs deliver α-toc by binding cell membrane receptor scavenger receptor class B type 1 (SR-B1) to prevent PL oxidation and ferroptosis. Additionally, data show Au-HDL NP, previously shown to bind SR-B1, reduce GPx4, and induce ferroptosis can rescue cells from ferroptosis when synthesized to contain α-toc. Overall, our data demonstrate a tunable cellular redox axis whereby HDLs containing α-toc target SR-B1 to regulate sensitivity to ferroptosis.