在治疗性 microRNA（miRNA 或 miR）的开发过程中，定义其药理作用至关重要。相反，miRNA 研究和治疗主要使用体外合成的 miRNA 模拟物。对体内产生的独特重组 miRNA 进行实验筛选后，通过生物信息学分析发现，三种针对人类 NSCLC 细胞的主要抗增殖 miRNA（miR-22-3p、miR-9-5p 和 miR-218-5p）可靶向叶酸代谢。重组 miR-22-3p、miR-9-5p 和 miR-218-5p 显示可调节关键叶酸代谢酶，从而抑制叶酸代谢，从而改变 NSCLC A549 和 H1975 细胞中的氨基酸代谢组。同位素示踪研究进一步证实，所有三种 miRNA 均能破坏从丝氨酸到叶酸代谢物的一碳转移，miR-22-3p 抑制葡萄糖摄取，miR-9-5p 和 -218- 减少葡萄糖从丝氨酸生物合成。 NSCLC 细胞中的 5p。重组 miR-22-3p 比 miR-9-5p 和 -218-5p 具有更强的中断 NSCLC 细胞呼吸、糖酵解和集落形成的活性，可有效减少两种 NSCLC 患者来源的异种移植小鼠模型中的肿瘤生长，且不会引起任何副作用。毒性。这些结果建立了共同的抗叶酸机制、三种主要抗癌 miRNA 对葡萄糖摄取和代谢的差异作用以及 miR-22-3p 纳米药物的抗肿瘤功效，这将为开发抗代谢 RNA 疗法提供见解。© 2023 中国药学会中国医学科学院药物研究所.由 Elsevier B.V. 制作和主持

During the development of therapeutic microRNAs (miRNAs or miRs), it is essential to define their pharmacological actions. Rather, miRNA research and therapy mainly use miRNA mimics synthesized in vitro. After experimental screening of unique recombinant miRNAs produced in vivo, three lead antiproliferative miRNAs against human NSCLC cells, miR-22-3p, miR-9-5p, and miR-218-5p, were revealed to target folate metabolism by bioinformatic analyses. Recombinant miR-22-3p, miR-9-5p, and miR-218-5p were shown to regulate key folate metabolic enzymes to inhibit folate metabolism and subsequently alter amino acid metabolome in NSCLC A549 and H1975 cells. Isotope tracing studies further confirmed the disruption of one-carbon transfer from serine to folate metabolites by all three miRNAs, inhibition of glucose uptake by miR-22-3p, and reduction of serine biosynthesis from glucose by miR-9-5p and -218-5p in NSCLC cells. With greater activities to interrupt NSCLC cell respiration, glycolysis, and colony formation than miR-9-5p and -218-5p, recombinant miR-22-3p was effective to reduce tumor growth in two NSCLC patient-derived xenograft mouse models without causing any toxicity. These results establish a common antifolate mechanism and differential actions on glucose uptake and metabolism for three lead anticancer miRNAs as well as antitumor efficacy for miR-22-3p nanomedicine, which shall provide insight into developing antimetabolite RNA therapies.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.