Defense systems to avoid ferroptosis caused by lipid peroxidation-mediated membrane damage

Abstract

The presence of hydrogen peroxide along with ferrous iron produces hydroxyl radicals that preferably oxidize polyunsaturated fatty acids (PUFA) to alkyl radicals (L•). The reaction of L• with an oxygen molecule produces lipid peroxyl radical (LOO•) that collectively trigger chain reactions, which results in the accumulation of lipid peroxidation products (LOOH). Oxygenase enzymes, such as lipoxygenase, also stimulate the peroxidation of PUFA. The production of phospholipid hydroperoxides (P-LOOH) can result in the destruction of the architecture of cell membranes and ultimate cell death. This iron-dependent regulated cell death is generally referred to as ferroptosis. Radical scavengers, which include tocopherol and nitric oxide (•NO), react with lipid radicals and terminate the chain reaction. When tocopherol reductively detoxifies lipid radicals, the resultant tocopherol radicals are recycled via reduction by coenzyme Q or ascorbate. CoQ radicals are reduced back by the anti-ferroptotic enzyme FSP1. •NO reacts with lipid radicals and produces less reactive nitroso compounds. The resulting P-LOOH is reductively detoxified by the action of glutathione peroxidase 4 (GPX4) or peroxiredoxin 6 (PRDX6). The hydrolytic removal of LOOH from P-LOOH by calcium-independent phospholipase A2 leads the preservation of membrane structure. While the expression of such protective genes or the presence of these anti-oxidant compounds serve to maintain a healthy condition, tumor cells employ them to make themselves resistant to anti-tumor treatments. Thus, these defense mechanisms against ferroptosis are protective in ordinary cells but are also potential targets for cancer treatment.

Keywords:

• Ferroptosis
• glutathione peroxidase
• ascorbate
• tocopherol
• nitric oxide
• coenzyme Q

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was funded by the JSPS KAKENHI Grant-in-Aid for Scientific Research (C) [21K06850] to J.F. and the YU-COE program [S6] to J.F. from Yamagata University.