Mass spectrometry-based single-cell lipidomics: Advancements, challenges, and the path forward

In the past decade, lipidomics, now recognized as standalone subdiscipline of metabolomics, has gained considerable attention. Due to its sensitivity and unparalleled versatility, mass spectrometry (MS) has emerged as the tool of choice for lipid identification and detection. Traditional MS-based lipidomics are performed on bulk cell samples. While informative, these bulk-scale cellular lipidome measurements mask cellular heterogeneity across seemingly homogeneous populations of cells. Unfortunately, single cell lipidomics methodology and analyses are considerably behind genomics, transcriptomics, and proteomics. Therefore, the cell-to-cell heterogeneity and related function remains largely unexplored for lipidomics. Herein, we review recent advances in MS-based single cell lipidomics. We also explore the root causes for the slow development of single-cell lipidomics techniques. We aim to provide insights on the pivotal knowledge gaps that have been neglected, prohibiting the propulsion of the single-cell lipidomics field forward, while also providing our perspective towards future methodologies that can pave a path forward.