Lipid peroxidation and lipid metabolism pathways

Lipid peroxidation and lipid metabolism pathways encompass the biochemical processes involved in the synthesis, modification, and degradation of lipids, which are essential for maintaining cellular membrane integrity and signaling (Ayala et al., 2014, Oxidative Medicine and Cellular Longevity). Lipid peroxidation specifically refers to the free radical-mediated chain reaction that degrades polyunsaturated fatty acids (PUFAs), leading to the formation of reactive lipid hydroperoxides and aldehydes like malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which can cause significant cellular damage (Gaschler & Stockwell, 2017, Nature Chemical Biology). These pathways are the central execution mechanism for ferroptosis, an iron-dependent form of regulated cell death that is distinct from apoptosis and necrosis (Dixon et al., 2012, Cell). Key regulatory nodes within these pathways include Glutathione peroxidase 4 (GPX4), which neutralizes lipid hydroperoxides, and Acyl-CoA synthetase long-chain family member 4 (ACSL4), which facilitates the incorporation of PUFAs into membranes (Doll et al., 2017, Nature Chemical Biology). Pharmacological modulation of these pathways is being explored for treating various diseases; for instance, GPX4 inhibitors are investigated as potential anti-cancer agents to induce ferroptosis in resistant tumors, while ferroptosis inhibitors like Ferrostatin-1 are studied for neuroprotection and treating ischemia-reperfusion injury (Stockwell et al., 2017, Cell).

Other names

Lipid peroxidationLipid metabolismFerroptosis pathwayFatty acid metabolismOxidative lipid degradation

Modulation of these pathways occurs through the inhibition of antioxidant enzymes like Glutathione peroxidase 4 (GPX4), the scavenging of lipid peroxyl radicals by lipophilic antioxidants, or the alteration of fatty acid composition in membranes by targeting enzymes such as Acyl-CoA synthetase long-chain family member 4 (ACSL4).