放射治疗是临床治疗肝细胞癌（HCC）患者的有效方法。然而，原发性和获得性放射抗性都限制了其在 HCC 中的临床应用。因此，研究放射抵抗机制可能为治疗 HCC 提供其他选择。基于单细胞RNA测序（scRNA-seq）和HCC转录组数据集，选择227个具有预后价值的特征基因来建立tSNE评分。 tSNE 评分成为 HCC 的独立预后因素，并与细胞增殖和放射抗性相关的生物学功能相关。 UBAP2 被确定为与 tSNE 评分最相关的基因，在人类 HCC 样本中持续升高，并且与患者预后呈正相关。从功能上讲，UBAP2 敲低可阻碍 HCC 的发展并降低体外和体内的辐射耐受性。 SLC27A5 的异位表达逆转了 UBAP2 的作用。从机制上讲，我们发现UBAP2通过泛素蛋白酶体系统，通过降解抑癌基因SLC27A5，减少同源重组相关基因RAD51，而不是非同源末端连接（NHEJ）相关基因CTIP，从而在HCC中产生放射抗性。研究结果概括了 UBAP2 通过泛素-蛋白酶体途径介导的 SLC27A5 稳定性促进 HCC 进展和放射抗性。还有人建议，针对 UBAP2/SLC27A5 轴可能是 HCC 中一种有价值的放射增敏策略。版权所有 © 2024。由 Elsevier B.V. 出版。

Radiotherapy stands as an effective method in the clinical treatment of hepatocellular carcinoma (HCC) patients. However, both primary and acquired radioresistance limit its clinical application in HCC. Therefore, investigating the mechanism of radioresistance may provide other options for treating HCC. Based on single-cell RNA sequencing (scRNA-seq) and HCC transcriptome datasets, 227 feature genes with prognostic value were selected to establish the tSNE score. The tSNE score emerged as an independent prognostic factor for HCC and correlated with cell proliferation and radioresistance-related biological functions. UBAP2 was identified as the most relevant gene with the tSNE score, consistently elevated in human HCC samples, and positively associated with patient prognosis. Functionally, UBAP2 knockdown impeded HCC development and reduced radiation resistance in vitro and in vivo. The ectopic expression of SLC27A5 reversed the effects of UBAP2. Mechanically, we uncovered that UBAP2, through the ubiquitin-proteasome system, decreased the homologous recombination-related gene RAD51, not the non-homologous end-joining (NHEJ)-related gene CTIP, by degrading the antioncogene SLC27A5, thereby generating radioresistance in HCC. The findings recapitulated that UBAP2 promoted HCC progression and radioresistance via SLC27A5 stability mediated by the ubiquitin-proteasome pathway. It was also suggested that targeting the UBAP2/SLC27A5 axis could be a valuable radiosensitization strategy in HCC.Copyright © 2024. Published by Elsevier B.V.