Chemical reaction-enabled lipidomics: from sensitive structural analysis to biomedical applications

Lipidomics has emerged as a vital discipline for understanding cellular metabolism and disease pathology. However, the immense structural diversity, wide dynamic range, and varying ionization efficiencies of lipids present significant analytical challenges. The MS analysis workflow often falls short in detecting low-abundance species and resolving complex structural isomers. To address these limitations, chemical derivatization has been widely adopted to manipulate the chemical properties of lipids prior to analysis. This review summarizes the significant progress in chemical derivatization-enabled lipidomics over the past decades, highlighting its pivotal role in bridging the gap between analytical capability and biological complexity. We critically discuss three core dimensions of improvement: (1) enhancement of detection sensitivity through derivatization strategies that increase the ionization efficiency of lipids; (2) refinement of structural elucidation, specifically using selective reactions to pinpoint carbon-carbon double bond locations and differentiate isomers; and (3) advancement of spectrometric specificity and quantification via mass-shift profiling, which enables precise quantification or high-throughput multiplex analysis. Finally, we discuss how these chemical tools are facilitating the discovery of novel lipid biomarkers and providing deeper insights into lipid metabolism in biomedical research.