天然深共熔溶剂（NADESs）正在成为传统有机溶剂的可持续替代品。除了作为实验室溶剂的角色外，NADESs在药物传递和治疗方面的应用越来越多。尽管应用越来越广泛，但我们对它们在人类细胞中与生物分子的相互作用的理解仍然不足，尤其在代谢组学、蛋白质组学和转录组学层面。在这里，我们运用综合代谢组学、蛋白质组学和转录组学的方法来研究NADESs如何干扰人类细胞的分子景观。在人类细胞系模型中，我们发现一种典型的由胆碱和天竺醛（CAGE）衍生的NADES显著改变了代谢组、蛋白质组和转录组。CAGE上调了吲哚-3-乳酸和4-羟基苯乳酸的水平，从而无需配体就激活了芳香烃水解酶受体，信号转录具有炎症、免疫调节、细胞发育和化学解毒相关的基因。此外，用CAGE处理细胞系使谷氨酰胺生物合成下调，谷氨酰胺是迅速增殖的癌细胞需要的营养物质。CAGE减弱谷氨酰胺水平的能力对癌症治疗可能具有相关意义。这些发现表明，即使从胆碱等天然成分衍生出来，NADESs也能间接调节细胞生物学的多个层面，将其应用扩展到化学之外的生物医学和生物技术领域。© 2023 Wiley-VCH GmbH.

Natural deep eutectic solvents (NADESs) are emerging sustainable alternatives to conventional organic solvents. Beyond their role as laboratory solvents, NADESs are increasingly explored in drug delivery and as therapeutics. Their increasing applications notwithstanding, our understanding of how they interact with biomolecules at multiple levels - metabolome, proteome, and transcriptome - within human cell remain poor. Here, we deploy integrated metabolomics, proteomics, and transcriptomics to probe how NADESs perturb the molecular landscape of human cells. In a human cell line model, we found that an archetypal NADES derived from choline and geranic acid (CAGE) significantly altered the metabolome, proteome, and transcriptome. CAGE upregulated indole-3-lactic acid and 4-hydroxyphenyllactic acid levels, resulting in ligand-independent activation of aryl hydrocarbon receptor to signal the transcription of genes with implications for inflammation, immunomodulation, cell development, and chemical detoxification. Further, treating the cell line with CAGE downregulated glutamine biosynthesis, a nutrient rapidly proliferating cancer cells require. The ability of CAGE to attenuate glutamine levels is potentially relevant for cancer treatment. These findings suggest that NADESs, even when derived from natural components like choline, can indirectly modulate cell biology at multiple levels, expanding their applications beyond chemistry to biomedicine and biotechnology.© 2023 Wiley-VCH GmbH.