Distinct metabolic profiles in lung adenocarcinomas presenting as solid or ground-glass opacities

Metabolomic profiling provides real-time insights into tissue physiology and upstream molecular events. Despite its potential in cancer research, large-scale integrative studies in lung adenocarcinoma (LUAD) remain scarce. We analyzed 262 tissue samples from 165 LUAD patients using metabolomic, transcriptomic, and 16S rRNA sequencing, integrating data through a “gene-enzyme-reaction-metabolite” network. Distinct components of mixed ground-glass opacities (mGGOs) and lesions from multiple primary lung cancers (MPLC) were also evaluated separately. Our results revealed extensive metabolic reprogramming in LUAD, predominantly affecting glycerophospholipid metabolism. Pure ground-glass opacities (GGOs) and solid nodules (SNs) exhibited markedly distinct metabolic profiles, with linoleic acid metabolism as a key differentiator. In contrast, components within mGGOs were metabolically similar, resembling pure GGOs. Cellular and organoid models demonstrated that phospholipase A2 (PLA2) inhibition or phosphatidylcholine (32:0) treatment significantly attenuated invasion and proliferation of LUAD cells. These findings provide a metabolic basis for subtype-specific LUAD biology and potential therapeutic strategies.