Bertoldi Agnese, Cusumano Gaia, Calzoni Eleonora, Alabed Husam B R, Pellegrino Roberto Maria, Buratta Sandra, Urbanelli Lorena, Emiliani Carla
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy.
Centro di Digitalizzazione del Patrimonio Culturale (CeDiPa), University of Perugia, 06123 Perugia, Italy.
Cells. 2025 Aug 10;14(16):1233. doi: 10.3390/cells14161233.
Epithelial-mesenchymal transition (EMT) is a key process in cancer progression and fibrogenesis. In this study, EMT was induced in Huh7 hepatocellular carcinoma cells via TGF-β1 treatment, and the resulting lipidomic and metabolomic alterations were characterized. Morphological changes and protein marker analyses confirmed the transition to a mesenchymal phenotype, with reduced E-cadherin and increased vimentin and N-cadherin expression. Lipidomic profiling revealed a dose-dependent reorganization of membrane lipids, with a pronounced increase in the levels of ceramides, cholesteryl esters, and lysophospholipids, consistent with alterations in membrane structure, potential cellular stress, and modulation of inflammatory pathways. Changes in the content of phospholipid classes, including phosphatidylethanolamines and phosphatidylserines, indicate possible variations in membrane dynamics and potentially point to modifications in mitochondrial function, cellular stress responses, and redox balance. Metabolomic analysis further indicates an alteration of choline and phosphatidylcholine metabolism, consistent with a shift from de novo membrane synthesis toward lipid turnover. Reduced glycolytic capacity and modified acylcarnitine levels indicated impaired metabolic flexibility and mitochondrial efficiency. The integration of phenotypic, lipidomic, and metabolomic data suggests that TGF-β1 induces EMT and drives a coordinated metabolic reprogramming. These findings highlight the involvement of lipid and energy metabolism in sustaining EMT and suggest that specific metabolic reprogramming events characterize the mesenchymal shift in hepatocellular carcinoma. By exploring this process in a tumor-specific context, we aim to deepen our understanding of EMT complexity and its implications for tumor progression and therapeutic vulnerability.
上皮-间质转化（EMT）是癌症进展和纤维化形成中的关键过程。在本研究中，通过TGF-β1处理在Huh7肝癌细胞中诱导EMT，并对由此产生的脂质组和代谢组改变进行了表征。形态学变化和蛋白质标志物分析证实了向间充质表型的转变，E-钙黏蛋白减少，波形蛋白和N-钙黏蛋白表达增加。脂质组分析揭示了膜脂的剂量依赖性重组，神经酰胺、胆固醇酯和溶血磷脂水平显著增加，这与膜结构改变、潜在的细胞应激和炎症途径的调节一致。磷脂类（包括磷脂酰乙醇胺和磷脂酰丝氨酸）含量的变化表明膜动力学可能存在变化，并可能指向线粒体功能、细胞应激反应和氧化还原平衡的改变。代谢组分析进一步表明胆碱和磷脂酰胆碱代谢发生改变，这与从从头合成膜向脂质周转的转变一致。糖酵解能力降低和酰基肉碱水平改变表明代谢灵活性和线粒体效率受损。表型、脂质组和代谢组数据的整合表明，TGF-β1诱导EMT并驱动协调的代谢重编程。这些发现突出了脂质和能量代谢在维持EMT中的作用，并表明特定的代谢重编程事件是肝癌间充质转变的特征。通过在肿瘤特异性背景下探索这一过程，我们旨在加深对EMT复杂性及其对肿瘤进展和治疗易感性影响的理解。
