Peroxidation rate constants and mechanisms of isoprenoid-derived lipids and their roles in ferroptosis

Abstract

Ferroptosis is a type of regulated cell death that is dependent on iron and driven by lipid peroxidation. Polyunsaturated fatty acids (PUFAs) sensitize cells to ferroptosis as they are prone to lipid peroxidation while monounsaturated fatty acids confer resistance to ferroptosis when incorporated into the lipid membrane as they are much less reactive toward lipid peroxidation. Recently, in addition to fatty acid-derived lipids, isoprenoid-derived lipids have been found to regulate ferroptosis. Specifically, ferroptosis suppressor protein 1 (FSP1) was found to be anti-ferroptotic as it reduces the oxidized forms of coenzyme Q₁₀ and vitamin K to their reduced quinol forms, which are phenolic radical-trapping antioxidants. Vitamins D₃ and A have also been found to inhibit ferroptosis in cancer cells. Furthermore, it has been shown that metabolites along the cholesterol synthesis pathway, including squalene, cholesterol, desmosterol, and 7-dehydrocholesterol (7-DHC), can protect cells against ferroptosis in vitro. Despite large variations in the reactivities of these lipids toward lipid peroxidation, they generally exhibit anti-ferroptotic properties. In this review, we will discuss the peroxidation rate constants and mechanisms of these isoprenoid-derived lipids and how they might contribute to their roles in ferroptosis.