针对葡萄糖和氧化代谢的双重干预在癌症治疗中受到越来越多的关注。索拉非尼（S）和二甲双胍（M）是肝癌的两种金标准，以其线粒体抑制能力而闻名。禁食是一种限制血糖的策略，也正在作为化疗辅助疗法出现。在此，我们探讨了营养限制与索拉非尼：二甲双胍 (NR-S:M) 组合的抗癌反应。我们的数据表明，与肝癌侵袭性无关，禁食可协同增强 S:M co 的抗增殖作用。 -治疗。通过检查线粒体和糖酵解活性、细胞周期调节、细胞凋亡激活以及关键信号传导和代谢酶的调节来确定代谢和细胞可塑性。在 NR-S:M 条件下，发现早期凋亡事件和促凋亡 Bcl-xS/Bcl-xL 比率增加。 NR-S:M 在细胞 SubG1 期诱导最高保留，与细胞凋亡 DNA 片段的存在一致。线粒体功能、线粒体 ATP 相关呼吸、最大呼吸和备用呼吸能力均在 NR-S:M 条件下减弱。基础糖酵解、糖酵解储备和糖酵解能力，以及糖原 (PKM)、糖异生 (PCK1 和 G6PC3) 和糖原分解酶 (PYGL、PGM1 和 G6PC3) 的表达，也受到 NR-S:M 的负面影响。最后，TMT 蛋白质组学方法证实了肝癌代谢重编程与分子途径激活的同步性，以驱动能量崩溃和细胞死亡的静止状态。总之，我们表明基于能量的多疗法 NR-S： M 削弱肝癌的细胞、代谢和分子可塑性。尽管这项研究是体外设计的，但它为这种肿瘤病理学提供了一种值得探索的有前景的治疗工具。© 2024。作者。

Dual-Interventions targeting glucose and oxidative metabolism are receiving increasing attention in cancer therapy. Sorafenib (S) and Metformin (M), two gold-standards in liver cancer, are known for their mitochondrial inhibitory capacity. Fasting, a glucose-limiting strategy, is also emerging as chemotherapy adjuvant. Herein, we explore the anti-carcinogenic response of nutrient restriction in combination with sorafenib:metformin (NR-S:M).Our data demonstrates that, independently of liver cancer aggressiveness, fasting synergistically boosts the anti-proliferative effects of S:M co-treatment. Metabolic and Cellular plasticity was determined by the examination of mitochondrial and glycolytic activity, cell cycle modulation, activation of cellular apoptosis, and regulation of key signaling and metabolic enzymes. Under NR-S:M conditions, early apoptotic events and the pro-apoptotic Bcl-xS/Bcl-xL ratio were found increased. NR-S:M induced the highest retention in cellular SubG1 phase, consistent with the presence of DNA fragments from cellular apoptosis. Mitochondrial functionality, Mitochondrial ATP-linked respiration, Maximal respiration and Spare respiratory capacity, were all found blunted under NR-S:M conditions. Basal Glycolysis, Glycolytic reserve, and glycolytic capacity, together with the expression of glycogenic (PKM), gluconeogenic (PCK1 and G6PC3), and glycogenolytic enzymes (PYGL, PGM1, and G6PC3), were also negatively impacted by NR-S:M. Lastly, a TMT-proteomic approach corroborated the synchronization of liver cancer metabolic reprogramming with the activation of molecular pathways to drive a quiescent-like status of energetic-collapse and cellular death.Altogether, we show that the energy-based polytherapy NR-S:M blunts cellular, metabolic and molecular plasticity of liver cancer. Notwithstanding the in vitro design of this study, it holds a promising therapeutic tool worthy of exploration for this tumor pathology.© 2024. The Author(s).