Protein modification by lipid-derived electrophiles (LDEs) associates with various signaling pathways. Among these LDEs, HNE, is the most toxic and proteins modification of HNE have been linked to various diseases, including Alzheimer's and Parkinson's. However, due to their low abundance, in-depth profiling of HNEs modifications still presents challenges. This study introduces a novel strategy utilizing reversible thiazolidine chemistry to selectively capture HNE-modified proteins and palladium-mediated cleavage reaction to release them. Thousands of HNE-modified sites in different cell lines were identified. Combined with ABPP, we discovered a set of HNE-sensitive sites, offers a new tool for studying LDEs modifications in proteomes.