Computationally unmasking each fatty acyl C=C position in complex lipids by routine LC-MS/MS lipidomics.

Journal: Nature communications
Published Date: Aug 11, 2025

Abstract

Identifying carbon-carbon double bond (C=C) positions in complex lipids is essential for elucidating physiological and pathological processes. Currently, this is impossible in high-throughput analyses of native lipids without specialized instrumentation that compromises ion yields. Here, we demonstrate automated, chain-specific identification of C=C positions in complex lipids based on the retention time derived from routine reverse-phase chromatography tandem mass spectrometry (RPLC-MS/MS). We introduce LC=CL, a computational solution that utilizes a comprehensive database capturing the elution profile of more than 2400 complex lipid species identified in RAW264.7 macrophages, including 1145 newly reported compounds. Using machine learning, LC=CL provides precise and automated C=C position assignments, adaptable to any suitable chromatographic condition. To illustrate the power of LC=CL, we re-evaluated previously published data and discovered new C=C position-dependent specificity of cytosolic phospholipase A (cPLA). Accordingly, C=C position information is now readily accessible for large-scale high-throughput studies with any MS/MS instrumentation and ion activation method.

Authors

  • Leonida M Lamp
    Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.
  • Gosia M Murawska
    Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
  • Joseph P Argus
    Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
  • Aaron M Armando
    Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
  • Radu A Talmazan
    Laboratoire de Physique et Chimie Théoriques, Université de Lorraine, Nancy, France.
  • Marlene Pühringer
    Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
  • Evelyn Rampler
    Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
  • Oswald Quehenberger
    Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
  • Edward A Dennis
    Department of Pharmacology, University of California San Diego, La Jolla, CA, USA. edennis@ucsd.edu.
  • Jürgen Hartler
    Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria. juergen.hartler@uni-graz.at.

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