Mechanistic principles of lipid oxidation: from hydroperoxide formation to secondary oxidation reactions

Lipid oxidation plays crucial roles in both food deterioration and biological processes. Despite extensive studies, the mechanistic principles governing the formation of oxidized lipids remain incompletely understood, largely due to the remarkable structural diversity of oxidation products. In this review, we discuss lipid oxidation from the perspective of chemical reactivity, focusing on the formation and decomposition of lipid hydroperoxides (LOOH) as primary oxidation products. We summarize the major oxidation mechanisms determining the positional distribution of hydroperoxyl groups, including radical, enzymatic, and singlet oxygen-mediated pathways. Recent advances in liquid chromatography-tandem mass spectrometry for structural analysis of LOOH isomers are also reviewed. Particular attention is given to mechanistic principles governing secondary oxidation reactions, where decomposition pathways are largely dictated by radical intermediate stability and surrounding double-bond topology. Integrating structural analysis with stability-based mechanistic principles provides a framework for understanding lipid oxidation and predicting diverse oxidized lipid species.