癌细胞的特点是细胞不受控制的增殖和受损的生物能调节。Sirtuins是一类高度保守的酶家族，在能量代谢调控中发挥着基本作用。特别是SIRT1在营养物质匮乏情况下引发许多生理应激反应和代谢途径。我们之前的研究表明，使用SCIC2.1激活SIRT1能够减轻毒物应答和细胞衰老。本文报告在葡萄糖缺乏条件下的肝细胞癌（HCC）细胞中，SCIC2.1处理能诱导SIRT1、SIRT3和SIRT6的过表达，调节代谢反应。我们使用流式细胞术分析细胞周期。使用MTT测定和xCELLigence系统测定细胞存活能力和增殖情况。根据制造商的指示进行体外酶学实验，并使用自动化Infinite M1000读取器测定吸光度。使用Western blotting和免疫沉淀评估本研究中所描述的各种蛋白质的表达。使用实时PCR研究基因的相对表达。使用Seahorse XF24分析仪确定细胞的代谢状态。使用Oil Red O染色测定脂质积累。SCIC2.1通过AMPK-p53-PGC1α途径显著促进线粒体生物合成，并在葡萄糖匮乏条件下增强线粒体ATP产生。Ex-527抑制SIRT1进一步支持了我们的假设，即代谢效应依赖于SIRT1的激活。有趣的是，SCIC2.1通过抑制脂新生重新编程葡萄糖代谢和脂肪酸氧化，以获得生物能电路。此外，SCIC2.1介导的SIRT1激活通过SIRT3激活强烈调节抗氧化应答，通过间接招募SIRT6调节p53依赖的应激反应。我们的结果表明，在葡萄糖匮乏情况下，SCIC2.1能促进能量稳态，通过激活SIRT1减轻代谢应激。这些发现揭示了SIRT1在HCC发病机制中的代谢作用，可能有助于确定该疾病以及其他代谢性疾病的未来治疗方法。© 2023年BioMed Central有限公司，Springer Nature的一部分。

Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response.Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation.SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by Ex-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6.Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases.© 2023. BioMed Central Ltd., part of Springer Nature.