Fluorescence-Guided Surface Plasmon Polarization Laser Desorption Mass Spectrometry Enables Targeted Single-Cell Lipidomic Profiling of Ferroptosis.

Authors

Qian An, Yongyi Li, Xiangyu Wang, Chengjian Qi, Haijie Wang, Wenxin Wang, Ruyu Ma, Zhenwei Wei

Published in

Analytical chemistry. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, manifests with pronounced single-cell heterogeneity that often dictates the cell fate. Conventional bulk-scale lipidomic analyses obscure early-stage oxidative signatures and intercellular stochasticity, while current single-cell mass spectrometry (MS) workflows are frequently hampered by nonselective sampling and severe ion suppression from biological matrices, leading to substantial experimental and computational overhead. To address these limitations, we developed a fluorescence-guided surface plasmon polarization laser desorption ionization mass spectrometry (SPP-LDI-MS) platform designed for the targeted collection and high-resolution lipidomic profiling of individual cells. This synergistic approach utilizes lipid peroxidation-responsive fluorescent probes to initially screen and define the oxidative trajectories of the cell population. Targeted single cells are subsequently captured and transferred onto the apex of a copper-coated tapered capillary via a custom-designed SPP-LDI probe. Within this microinterface, the surface plasmon polarization-enhanced electromagnetic fields facilitate the direct laser soft ionization of intracellular contents. We demonstrate that the SPP-LDI configuration effectively mitigates salt- and buffer-induced ion suppression, markedly elevating lipid detection sensitivity and molecular coverage at the single-cell level beyond the limits of traditional nESI methods. Application to an RSL3-induced ferroptosis model enabled the precise identification of doubly and triply oxidized polyunsaturated phospholipids at the single-cell level, the accumulation of which was reversibly modulated by selenomethionine (SeMet) intervention. This state-guided lipidomic strategy provides a robust analytical framework for resolving stage-specific lipid remodeling, offering new insights into the molecular mechanisms underlying cellular heterogeneity in ferroptotic pathways.

PMID:
42340265
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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