Resolving the Role of Lipoxygenases in the Initiation
and Execution of Ferroptosis
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Abstract
Lipoxygenases (LOXs)
have been implicated as central players in
ferroptosis, a recently characterized cell death modality associated
with the accumulation of lipid hydroperoxides: the products of LOX
catalysis. To provide insight on their role, human embryonic kidney
cells were transfected to overexpress each of the human isoforms associated
with disease, 5-LOX, p12-LOX, and 15-LOX-1, which yielded stable cell
lines that were demonstrably sensitized to ferroptosis. Interestingly,
the cells could be rescued by less than half of a diverse collection
of known LOX inhibitors. Furthermore, the cytoprotective compounds
were similarly potent in each of the cell lines even though some were
clearly isoform-selective LOX inhibitors. The cytoprotective compounds
were subsequently demonstrated to be effective radical-trapping antioxidants,
which protect lipids from autoxidation, the autocatalytic radical
chain reaction that produces lipid hydroperoxides. From these data
(and others reported herein), a picture emerges wherein LOX activity <i>may</i> contribute to the cellular pool of lipid hydroperoxides
that initiate ferroptosis, but lipid autoxidation drives the cell
death process