代谢重编程是癌症的一个重要标志，它通过允许肿瘤组织适应抗癌治疗引起的肿瘤微环境的变化来促进化疗耐药。肝细胞癌 (HCC) 是最常见的原发性肿瘤类型之一，与复发性代谢重编程相关，从而最大限度地促进癌细胞生长和增殖。在此，我们通过简单、绿色的方法开发了负载二甲双胍（MET）的透明质酸（HA）衍生的碳点（HA-CD-MET），不涉及任何添加剂。 HA-CD-MET 用于特异性结合 HCC 中过度表达的 CD44 受体，并诱导谷氨酰胺代谢重连，从而抑制 HCC 细胞增殖。与 CD44-、HepG2 和非癌性 HEK293 细胞相比，在 80 μg/mL 的极低剂量下，暴露于 HA-CD-MET 可使 CD44 Hep3B 细胞的抗癌功效提高约 6.5 倍。此外，用 HA-CD-MET 治疗 HCC (Hep3B) 三维 (3D) 肿瘤球体模型可使肿瘤大小缩小约 4.9 倍。 HA-CD-MET 抗癌功效的提高归因于谷氨酰胺酶-1 (GLS-1) 的抑制，免疫荧光和免疫印迹实验证实，谷氨酰胺酶-1 是一种将谷氨酰胺水解成谷氨酸的线粒体酶。此外，HA-CD-MET 治疗导致 Hep3B 细胞中葡萄糖转运蛋白 1 (GLUT-1) 下调。因此，癌细胞缺乏必需的营养物质、谷氨酰胺和葡萄糖，导致细胞内活性氧生成增加。细胞内 ROS 积累的增加激活了 AMP 激活蛋白激酶 (AMPK) 并抑制 AKT 磷酸化，导致癌细胞凋亡。因此，这项研究提供了 HA-CD-MET 代谢重编程的靶向，为肝癌的治疗干预开辟了一种有前途的策略。

Metabolic reprogramming is a significant hallmark of cancer that promotes chemoresistance by allowing tumor tissues to adapt to changes in the tumor microenvironment caused by anticancer therapies. Hepatocellular carcinoma (HCC), one of the most common types of primary tumors, is associated with recurrent metabolic reprogramming that maximizes cancer cell growth and proliferation. Herein, we developed metformin (MET)-loaded hyaluronic acid (HA)-derived carbon dots (HA-CD-MET) by a simple and green method with no involvement of any additives. HA-CD-MET was utilized for specifically binding the CD44 receptor overexpressed in HCC and induced glutamine metabolic rewiring to inhibit HCC cell proliferation. Exposure to HA-CD-MET resulted in ∼6.5-fold better anticancer efficacy against CD44+ Hep3B cells in comparison to CD44-, HepG2, and noncancerous HEK293 cells at a very low dose of 80 μg/mL. Moreover, treatment of three-dimensional (3D) tumor spheroid model of HCC (Hep3B) with HA-CD-MET resulted in ∼4.9-fold reduction in tumor size. This improved anticancer efficacy of HA-CD-MET was attributed to the inhibition of glutaminase-1 (GLS-1), a mitochondrial enzyme that hydrolyzes glutamine into glutamate as confirmed from immunofluorescence and immunoblotting experiments. Furthermore, treatment with HA-CD-MET resulted in downregulation of glucose transporter-1 (GLUT-1) in Hep3B cells. Consequently, cancer cells were starved from essential nutrients, glutamine, and glucose, leading to the enhancement in intracellular ROS generation. This increase in intracellular ROS accumulation activated AMP-activated protein kinase (AMPK) and inhibited AKT phosphorylation, leading to cancer cell apoptosis. Thus, this study offers the targeting of metabolic reprogramming by HA-CD-MET that opens up a promising strategy for therapeutic intervention in hepatocarcinoma.