Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis

By Ron Shah, M. Shchepinov, D. Pratt. ACS Central Science, 2018

703 citations recorded by the source corpus.

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 may contribute to the cellular pool of lipid hydroperoxides that initiate ferroptosis, but lipid autoxidation drives the cell death process.

View Paper: https://www.semanticscholar.org/paper/57afd432e3d409305be7470e9f7c5267e1271739

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Citations in the corpus

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, unknown): “Iron regulation: Iron-driven lipid peroxidation The peroxidation ofmembrane-bound, PUFA-containing lipids is driven by both the labile iron pool facilitating the Fenton reaction, which propagates lipid peroxidation (Shah et al., 2018), and by iron-dependent enzymes, such as arachidonate lipoxygenase”
Emerging mechanisms and disease relevance of ferroptosis (2020, background): “these peroxides to drive overwhelming lipid peroxidation [20,21].”
Molecular mechanisms of cell death in neurological diseases (2021, background): “exhibit significant potential to directly inhibit lipid peroxidation [109].”
Ferroptosis in cancer therapy: a novel approach to reversing drug resistance (2022, background): “LOX inhibitors have also been demonstrated to be effective antioxidants that protect cells from lipid peroxidation [30].”
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “44,72 Enzymatic lipid peroxidation of PUFA-PLs primarily involves the action of ALOXs and cytochrome P450 oxidoreductase (POR).”