代谢重新塑造综合症是肝细胞癌（HCC）治疗的一种潜在有希望的策略。对谷氨酰胺转运蛋氨酸-丝氨酸-半胱氨酸转运体2（ASCT2）的调控有深入的理解，有助于新型有希望的治疗方法的发展。作为一种发育调控的RNA结合蛋白，RBM45能够在细胞核和细胞质之间穿梭，并直接与蛋白质相互作用。通过生物信息学分析，我们筛选出RBM45在HCC患者标本中升高，并与不良预后呈正相关。RBM45促进细胞增殖，增强异种移植的肿瘤形成能力，并加速HCC的进展。通过无靶代谢组学分析发现，RBM45干扰了谷氨酰胺代谢。进一步的结果表明，RBM45在人类和小鼠标本中与ASCT2呈正相关。此外，RBM45通过对抗自噬独立的溶酶体降解，增强ASCT2蛋白的稳定性。值得注意的是，野生型ASCT2，而不是磷酸缺陷突变体，恢复了siRBM45抑制的HCC细胞增殖。通过分子对接方法，我们发现AG-221，一种用于急性髓系白血病治疗的突变异柠檬酸脱氢酶2（mIDH2）抑制剂，药理学上干扰了RBM45-ASCT2相互作用，降低了ASCT2的稳定性并抑制了HCC的进展。这些发现提供了RBM45通过相互作用并对抗ASCT2降解在HCC进展中发挥关键作用的证据。我们的发现为设计ASCT2抑制剂和干扰RBM45-ASCT2相互作用的药物提供了一种新的替代结构位点，并可能成为HCC药物开发的潜在方向。©2023年，作者，独家授权给Springer Nature有限公司。

Targeting metabolic remodeling represents a potentially promising strategy for hepatocellular carcinoma (HCC) therapy. In-depth understanding on the regulation of the glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2) contributes to the development of novel promising therapeutics. As a developmentally regulated RNA binding protein, RBM45 is capable to shuttle between nucleus and cytoplasm, and directly interacts with proteins. By bioinformatics analysis, we screened out that RBM45 was elevated in the HCC patient specimens and positively correlated with poor prognosis. RBM45 promoted cell proliferation, boosted xenograft tumorigenicity and accelerated HCC progression. Using untargeted metabolomics, it was found that RBM45 interfered with glutamine metabolism. Further results demonstrated that RBM45 positively associated with ASCT2 in human and mouse specimens. Moreover, RBM45 enhanced ASCT2 protein stability by counteracting autophagy-independent lysosomal degradation. Significantly, wild-type ASCT2, instead of phospho-defective mutants, rescued siRBM45-suppressed HCC cell proliferation. Using molecular docking approaches, we found AG-221, a mutant isocitrate dehydrogenase 2 (mIDH2) inhibitor for acute myeloid leukemia therapy, pharmacologically perturbed RBM45-ASCT2 interaction, decreased ASCT2 stability and suppressed HCC progression. These findings provide evidence that RBM45 plays a crucial role in HCC progression via interacting with and counteracting the degradation of ASCT2. Our findings suggest a novel alternative structural sites for the design of ASCT2 inhibitors and the agents interfering with RBM45-ASCT2 interaction may be a potential direction for HCC drug development.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.