Pedox imbalance in cells induces lipid peroxidation and generate a class of highly reactive metabolites known as lipid-derived electrophiles(LDEs)that can modify proteins and affects their functions.Identifying targets of LDEs is critical to understand how such modification are functionally implicated in oxidative-stress associated diseases.Here we report a quantitative chemoproteomic method to globally profile protein targets and sites modified by LDEs.In this strategy,we designed and synthesized an alkyne-functionalized aminooxy probe to react with LDE-modified proteins for imaging and proteomic profiling.Using this probe we successfully quantifieo >4000 proteins modified by 4-hydroxy-2-nonenal(HNE)of high confidence in mammallan cell lysate and combined with a tandem-orthogonal proteolysis activity-based protein profiling(TOP-ABPP)strategy,we identified~400 residue sites targeted by HNE including reactive cysteines in peroxiredoxins,an important family of enzymes with anti-oxidant roles.