A metabolomics and lipidomics atlas of pulmonary large cell neuroendocrine carcinoma

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive lung cancer with limited therapeutic options and poorly defined metabolic features. To establish a comprehensive molecular overview, we generated the first metabolomics and lipidomics atlas of LCNEC using paired tumor and adjacent non-tumor lung tissues from 34 patients. Untargeted multiplatform liquid chromatography-mass spectrometry profiled 1052 metabolites, revealing extensive remodeling of amino acid, nucleotide, and lipid metabolism. Tumor tissues showed pronounced accumulation of both D- and L-2-hydroxyglutaric acid, indicating altered α-ketoglutarate metabolism independent of IDH1/2 mutations. Newly identified N-lactoyl-amino acids, formed via CNDP2-mediated condensation of lactate and amino acids, were uniformly elevated, suggesting enhanced lactoyl conjugation under elevated lactate levels. Lipidomic profiling revealed widespread reprogramming, including increased phosphatidylcholines, ether-linked phospholipids, polyunsaturated bis(monoacylglycero)phosphates, long-chain triacylglycerols, cholesteryl esters, and acylcarnitines, indicative of lysosomal remodeling and altered mitochondrial fatty acid transport. In addition, the nicotine metabolite cotinine was quantified as an objective biomarker of smoking exposure, revealing discrepancies between measured cotinine levels and self-reported smoking status in several patients. This highlights the value of metabolomics for independently verifying clinical information. Collectively, these data define a hybrid metabolic phenotype bridging features of small and non-small cell lung cancer while revealing unique metabolic signatures of LCNEC. The resulting atlas provides a foundational resource for biomarker discovery and the development of metabolism-based therapeutic strategies in this understudied lung cancer subtype.