Deep structural lipidomic profiling reveals C=C positional isomers as potential biomarkers in lung adenocarcinoma tissue.

Background: Recent evidence highlights the importance of lipid metabolic reprogramming in lung adenocarcinoma (LUAD) progression. Due to the limitations of conventional techniques, the fine structure of lipids cannot be identified. The metabolic changes of lipid structural features-particularly carbon-carbon double bond (C=C) positional isomers-remain underexplored. This study aims to characterize the structural alterations of lipids, especially C=C positional isomers, in LUAD tissues to elucidate their potential roles in tumor progression. Methods: We performed deep structural lipidomic profiling on paired normal lung (N) and LUAD (T) tissue samples using a combination of photochemical reaction-based structural analysis (Ω Analyzer) and liquid chromatography-mass spectrometry (LC-MS). Lipid species were characterized at three structural levels: lipid class, molecular species, and C=C positional isomer. Relative quantitative analyses were conducted to identify differences in total composition, unsaturation levels, and the distribution of C=C isomers between N and T groups. Results: A total of 794 phospholipid species were identified at the C=C isomer level, with the T group exhibiting a slightly higher overall number of identified lipids compared to the N group. Polyunsaturated lipids displayed notable upregulation in the T group and facilitated robust clustering between normal and cancer tissues. Furthermore, analyzing C=C positional isomers revealed significant differences in their relative abundances between the two groups: lipids enriched in C18:1(Δ9) were predominantly upregulated in T group samples, whereas those carrying C18:1(Δ8) were generally downregulated. Conclusions: Our findings demonstrate that deep structural lipidomic analysis yields crucial insights into the lipid reprogramming of LUAD. In particular, the relative abundances of C=C positional isomers hold promise as novel diagnostic markers and therapeutic targets for LUAD.