长链非编码RNA（lncRNA）在癌症不同生物学功能中发挥重要作用。然而，在人类肝细胞癌（HCC）患者的葡萄糖代谢中，它们的功能仍然大多未知。本研究利用HCC及配对完好的肝组织，通过qRT-PCR检测miR4458HG表达，并利用人类HCC细胞系，在转染siRNAs靶向miR4458HG或miR4458HG载体后，检测细胞增殖、集落形成和糖酵解。通过原位杂交、Western印迹、qRT-PCR、RNA pull-down和RNA免疫沉淀分析明确miR4458HG的分子机制。结果表明，miR4458HG影响了HCC细胞增殖，激活了糖酵解途径，在体内外模型中促进了肿瘤相关巨噬细胞的极化。miR4458HG通过结合IGF2BP2（关键的RNA m6A阅读器）并促进IGF2BP2介导的目标mRNA稳定性，包括HK2和SLC2A1（GLUT1），从而改变了HCC的糖酵解和肿瘤细胞生理。同时，HCC来源的miR4458HG可以包装在外泌体中，通过增加ARG1表达促进肿瘤相关巨噬细胞的极化。因此，miR4458HG在HCC患者中是致癌性的。为了开发有效的HCC治疗策略，医生应关注miR4458HG及其途径。 © 2023作者，独家许可Springer Nature Switzerland AG。

Long non-coding RNAs (lncRNAs) play significant roles in different biological functions of cancers. However, their function in the metabolism of glucose in patients with human hepatocellular carcinoma (HCC) remains largely unknown. In this study, HCC and paired intact liver tissues were utilized to examine the miR4458HG expression using qRT-PCR and human HCC cell lines to examine cell proliferation, colony formation, and glycolysis after transfection of siRNAs targeting miR4458HG or miR4458HG vectors. The molecular mechanism of miR4458HG was clarified through in situ hybridization, Western blotting, qRT-PCR, RNA pull-down, and RNA immunoprecipitation analysis. The results showed that the miR4458HG affected HCC cell proliferation, activated the glycolysis pathway, and promoted the polarization of tumor-associated macrophage in vitro and in vivo models. Mechanistically, miR4458HG bound IGF2BP2 (a key RNA m6A reader) and facilitated IGF2BP2-mediated target mRNA stability, including HK2 and SLC2A1 (GLUT1), and consequently altered HCC glycolysis and tumor cell physiology. At the same time, HCC-derived miR4458HG could be wrapped in the exosomes and promoted the polarization of tumor-associated macrophage by increasing ARG1 expression. Hence, miR4458HG is oncogenic in nature among patients with HCC. To develop an effective treatment strategy of HCC patients presenting with high glucose metabolism, physicians should focus on miR4458HG and its pathway.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.