甘草素（ISL）是一种天然黄酮类化合物，具有抗肿瘤活性。然而，对于ISL对胃癌（GC）生长的影响及其分子机制的理解仍然有限。本研究旨在探讨ISL对GC生长的抑制作用，同时阐明其分子机制。细胞活力通过细胞计数试剂盒-8（CCK-8）试验检测。体外的凋亡细胞通过Hoechst 33，342试剂监测。蛋白质表达通过Western blot进行评估。利用2'，7'-二氯荧光素二乙酸酯（DCFH-DA）评估活性氧（ROS）水平。L-乳酸检测试剂盒检测乳酸水平。通过标记荧光的葡萄糖2-[N-(7-硝基苯并[2-氧哌啶-4-基]氨基)-2-脱氧葡萄糖（2-NBDG）监测葡萄糖摄取。通过糖酵解效应质子外流速率（GlycoPER）检测糖酵解速率试剂盒进行评估。通过线粒体应力试验盒进行氧气消耗速率（OCR）测定。通过皮下注射MGC803细胞建立裸鼠胃癌细胞异种移植模型。通过H&E染色评估病理变化。通过末端脱氧核苷酸转移酶介导的dUTP末端标记（TUNEL）试验评估体内细胞凋亡。ISL显著抑制GC生长并增加细胞凋亡。其在体外和体内调节与凋亡和代谢相关的蛋白质表达。ISL阻断了葡萄糖摄取，抑制了乳酸的产生和分泌，伴随着线粒体氧化磷酸化（OXPHOS）和糖酵解的抑制，但增加了ROS的积累。过表达过氧化物酶体增殖物激活受体γ共激活蛋白-1α（PGC-1α）、细胞骨髓瘤浸润性病毒致癌基因（c-Myc）、缺氧诱导因子-1α（HIF-1α）、葡萄糖转运蛋白4（GLUT4）或丙酮酸脱氢酶激酶1（PDHK1），可以消除ISL对GC细胞生存能力的抑制作用。这些发现表明，ISL通过降低GLUT4介导的葡萄糖摄取和诱导PDHK1/PGC-1α介导的能量代谢崩溃，通过抑制c-Myc和HIF-1α的蛋白质表达来抑制GC生长，表明其在GC治疗中的潜在应用。版权所有©2023 Elsevier GmbH。保留所有权利。

Isoliquiritigenin (ISL), a natural flavonoid, has anti-tumor activity. But, the understanding of the impact and molecular mechanism of ISL on the growth of gastric cancer (GC) remains limited.The study was to explore the tumor suppressive effect of ISL on GC growth both in vitro and in vivo, meanwhile, clarify its molecular mechanisms.Cell viability was detected by cell counting kit-8 (CCK-8) assay. Apoptotic cells in vitro were monitored by Hoechst 33,342 solution. Protein expression was assessed by Western blot. Reactive oxygen species (ROS) level was evaluated by utilizing 2',7'- dichlorofluorescin diacetate (DCFH-DA). Lactic acid level was detected with L-lactate assay kit. Glucose uptake was monitored with fluorescently tagged glucose 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Glycolytic proton efflux rate (GlycoPER) was evaluated by glycolytic rate assay kit. Oxygen consumption rate (OCR) was conducted by mito stress test kit. A nude mouse model of gastric cancer cell xenograft was established by subcutaneous injection with MGC803 cells. Pathological changes were evaluated by using H&E staining. Cell apoptosis in vivo was evaluated by terminal deoxy-nucleotide transferase mediated dUTP nick end labeling (TUNEL) assay.ISL remarkably suppressed GC growth and increased cell apoptosis. It regulated apoptosis-related and metabolism-related protein expression both in vitro and in vivo. ISL blocked glucose uptake and suppressed production and secretion of lactic acid, which was accompanied with suppressed mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis but increased ROS accumulation. Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), cellular-myelocytomatosis viral oncogene (c-Myc), hypoxia inducible factor-1α (HIF-1α), glucose transporter 4 (GLUT4) or pyruvate dehydrogenase kinase 1 (PDHK1), could abolish ISL-induced inhibition of cell viability in GC cells.These findings implicated that ISL inhibits GC growth by decreasing GLUT4 mediated glucose uptake and inducing PDHK1/PGC-1α-mediated energy metabolic collapse through depressing protein expression of c-Myc and HIF-1α in GC, suggesting its potential application for GC treatment.Copyright © 2023 Elsevier GmbH. All rights reserved.