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ABSTRACT Lipids, indispensable yet structurally intricate biomolecules, serve as critical regulators of cellular function and disease progression. Conventional lipidomics, constrained by limited resolution for isomeric and low‐abundance species, has been transformed by ion mobility‐mass spectrometry (IM‐MS). This technology augments analytical power through enhanced orthogonal separation, collision cross‐section (CCS)‐based identification, and improved sensitivity. This review examines the transformative advances in IM‐MS‐driven lipidomics, focusing on three major pillars: (1) a critical evaluation of leading ion mobility spectrometry (IMS) platforms, emphasizing innovative instrument geometries and breakthroughs in resolving lipid isomers; (2) an exploration of lipid CCS databases and predictive frameworks, spotlighting computational modeling and machine learning strategies that synergize experimental data with molecular representations for high‐confidence lipid annotation; (3) emerging multi‐dimensional lipidomics workflows integrating CCS with liquid chromatography‐MS/MS to boost identification and depth, alongside mass spectrometry imaging for spatially resolved lipidomics. By unifying cutting‐edge instrumentation, computational advances, and biological insights, this review outlines a roadmap for leveraging IM‐MS to unravel lipidome complexity, catalyzing biomarker discovery and precision medicine innovation. 

Growing evidence supports the confident association between distinct amyloid beta (Aβ) isoforms and Alzheimer's Disease (AD) pathogenesis. As such, critical investigations seeking to uncover the translational factors contributing to Aβ toxicity represent a venture of significant value. Herein, we comprehensively assess full-length Aβ42 stereochemistry, with a specific focus on models that consider naturally-occurring isomerization of Asp and Ser residues. We customize various forms of d -isomerized Aβ as natural mimics, ranging from fragments containing a single d residue to full length Aβ42 that includes multiple isomerized residues, systematically evaluating their cytotoxicity against a neuronal cell line. Combining multidimensional ion mobility-mass spectrometry experimental data with replica exchange molecular dynamics simulations, we confirm that co- d -epimerization at Asp and Ser residues within Aβ42 in both N-terminal and core regions effectively reduces its cytotoxicity. We provide evidence that this rescuing effect is associated with the differential and domain-specific compaction and remodeling of Aβ42 secondary structure.