Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression.
Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression.
WMK-1 and WMK-2, tetraoxane-based metabolic initiators of lipid peroxidation (MILPOs), trigger a mitochondrial ferroptosis sub-pathway that does not require GPX4 inhibition and evades protection by retinol or long-chain PUFA supplementation. WMK-1 localizes to mitochondria, drives local lipid peroxidation, impairs oxidative phosphorylation, and depends on labile Fe2+, with cell death suppressed by the mitochondria-resident antioxidant alpha-lipoic acid. In multiple cancer models the bioavailable compounds suppress tumors and augment the effects of immune-checkpoint blockers.
It offers a protein-targeting-free way to induce ferroptosis in vivo, bypassing GPX4 and FSP1 resistance routes.
Source: Cell · doi.org