Lipid peroxidation targets (LPO targets)

Lipid peroxidation targets refer to a group of proteins and enzymes that regulate the oxidative degradation of polyunsaturated fatty acids (PUFAs), a process central to the regulated cell death pathway known as ferroptosis [7, 20]. The primary therapeutic target within this group is Glutathione peroxidase 4 (GPX4), a selenoprotein that reduces toxic lipid hydroperoxides to non-toxic lipid alcohols using glutathione as a cofactor [12, 18]. Other key targets include the cystine/glutamate antiporter (System Xc-), which provides the precursor for glutathione synthesis, and pro-oxidant enzymes such as lipoxygenases (e.g., ALOX12, ALOX15) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) that facilitate the production of peroxidizable lipids [3, 20, 23]. Dysregulation of these targets is implicated in numerous diseases, including cancer, neurodegenerative disorders, and cardiovascular ischemia-reperfusion injury [2, 14, 21]. In oncology, inducing lipid peroxidation by inhibiting GPX4 or System Xc- is a strategy to kill therapy-resistant cells [3, 15]. Conversely, in degenerative conditions, inhibiting lipid peroxidation using radical-trapping antioxidants (e.g., Ferrostatin-1) or iron chelators aims to prevent tissue damage [5, 20]. A major therapeutic challenge is the essentiality of GPX4 for normal cellular function, as its systemic inhibition can lead to severe toxicity and organ failure [14]. Additionally, achieving tissue-specific modulation remains a significant hurdle in the development of safe and effective therapies targeting this pathway [11].

Other names

Ferroptosis-regulating proteinsLipid hydroperoxide regulatorsOxidative stress targetsLPO targets

Inhibition of GPX4, inhibition of System Xc-, scavenging of lipid peroxyl radicals, iron chelation, and inhibition of lipoxygenases.