apelin 受体 (APJ) 是肿瘤血管生成的关键参与者，但其在肝细胞癌 (HCC) 中的作用仍不清楚。本研究旨在利用多组学方法阐明 Apelin/APJ 通路在 HCC 中的功能，并确定潜在的治疗生物标志物。从大量转录组学中鉴定出与 apelin/APJ 轴相关的差异表达基因，以揭示与 HCC 相关的差异。单细胞和空间转录组学用于定位和分析这些基因的功能。构建机器学习模型以根据 apelin/APJ 表达预测结果，并进行实验验证以探索该途径对 HCC 血管生成的影响。单细胞分析显示内皮细胞中 APJ/Aplin 过度表达。高apelin/APJ的内皮细胞(EC)干性增强，TGFb、氧化应激和PI3K/AKT通路基因的表达也增强。空间转录组学证实，具有高 APJ 评分的 EC 群体在肿瘤内富集。机器学习模型显示出很高的预测准确性。 APJ 高表达与较差的结果相关 (p=0.001)，AUC 值较高 (1 年、3 年、5 年) (0.95、0.97、0.98)。在高危人群中也出现了免疫抑制和免疫治疗无反应的情况。实验验证表明，沉默 apelin 会减少血管生成 (p<0.05)、内皮增殖，降低 ANG2、KLF2、VEGFA 的表达并降低 ERK1/2 磷酸化。鉴于 Apelin 在促进肿瘤血管生成和不良患者预后方面的作用，它可能成为 HCC 的潜在治疗靶点。© 2024 作者。细胞与分子医学基金会和约翰·威利出版的《细胞与分子医学杂志》

The apelin receptor (APJ) is a key player in tumour angiogenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to elucidate the function of the apelin/APJ pathway in HCC using a multi-omics approach and identify potential therapeutic biomarkers. Differentially expressed genes related to the apelin/APJ axis were identified from bulk transcriptomics to reveal HCC-associated disparities. Single-cell and spatial transcriptomics were used to localize and analyse the function of these genes. Machine learning models were constructed to predict outcomes based on apelin/APJ expression, and experimental validation was conducted to explore the pathway's impact on HCC angiogenesis. Single cell analysis revealed an overexpression of APJ/Aplin in the endothelium. The stemness of endothelial cell (EC) with high apelin/APJ was enhanced, as well as the expression of TGFb, oxidative stresses and PI3K/AKT pathway genes. Spatial transcriptomics confirmed that EC populations with high APJ scores were enriched within the tumour. Machine learning models showed high prognostic accuracy. High APJ expression was linked to worse outcomes (p = 0.001), and AUC values were high (1 year, 3 year, 5 year) (0.95, 0.97, 0.98). Immune suppression and non-responsiveness of immune therapy were also seen in high-risk groups. The experimental validation showed that silencing apelin reduced angiogenesis (p  < 0.05), endothelial proliferation, decreased expression of ANG2, KLF2, VEGFA and lower ERK1/2 phosphorylation. Apelin may serve as a potential therapeutic target in HCC, given its role in promoting tumour angiogenesis and poor patient outcomes.© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.