Language model-guided anticipation and discovery of unknown metabolites.

Despite decades of study, large parts of the mammalian metabolome remain unexplored. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks within human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains a low-throughput endeavor. Biochemical large language models have transformed the interpretation of DNA, RNA, and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism.

Phospholipid isotope tracing suggests β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma.

Activating mutations in the CTNNB1 gene encoding β-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). Profound alterations in lipid metabolism, including increases in fatty acid oxidation and transformation of the phospholipidome, occur in HCC with CTNNB1 mutations, but it is unclear what mechanisms give rise to these changes. We employed untargeted lipidomics and targeted isotope tracing to measure phospholipid synthesis activity in an inducible human liver cell line expressing mutant β-catenin, as well as in transgenic zebrafish with activated β-catenin-driven HCC.

Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma.

Background And Aims: Activating mutations in the gene encoding β-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). HCC with mutations show profound alterations in lipid metabolism including increases in fatty acid oxidation and transformation of the phospholipidome, but it is unclear how these changes arise and whether they contribute to the oncogenic program in HCC.

Methods: We employed untargeted lipidomics and targeted isotope tracing to quantify phospholipid production fluxes in an inducible human liver cell line expressing mutant β-catenin, as well as in transgenic zebrafish with activated β-catenin-driven HCC.