Gao Shuang, Fan Lulu, Wang Huiyan, Wang Anqi, Hu Mengyao, Zhang Lei, Sun Guoping
Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230001, China.
Cell Death Discov. 2025 May 2;11(1):215. doi: 10.1038/s41420-025-02473-1.
NCOA5 has been identified as a crucial factor in the progression of hepatocellular carcinoma (HCC). This study investigates the expression of NCOA5 in HCC, revealing its significant overexpression in tumor tissues compared to healthy liver tissues, as evidenced by analysis of the TCGA dataset and RT-qPCR in patient samples. Higher NCOA5 levels correlate with poor overall survival, highlighting its role as a prognostic indicator. Furthermore, our findings suggest that elevated NCOA5 is associated with resistance to sorafenib, a common chemotherapeutic agent for HCC, as shown through analysis of publicly available datasets and the establishment of sorafenib-resistant HCC cell lines. Mechanistically, NCOA5 appears to inhibit ferroptosis in HCC cells by modulating glutathione peroxidase 4 (GPX4) levels. Knockdown of NCOA5 sensitizes resistant cell lines to sorafenib and induces ferroptosis by decreasing GPX4 expression. Additionally, NCOA5 regulation of GPX4 is mediated through the transcription factor MYC. In vivo studies further validate that targeting NCOA5 enhances the efficacy of sorafenib in resistant HCC models by promoting ferroptosis. Collectively, these findings underscore the potential of NCOA5 as a therapeutic target to overcome drug resistance in HCC, providing insights into its role in modulating treatment responses and patient prognosis.
NCOA5已被确定为肝细胞癌（HCC）进展的关键因素。本研究调查了NCOA5在HCC中的表达，通过对TCGA数据集的分析以及患者样本中的RT-qPCR证明，与健康肝组织相比，其在肿瘤组织中显著过表达。较高的NCOA5水平与较差的总生存期相关，突出了其作为预后指标的作用。此外，我们的研究结果表明，通过对公开可用数据集的分析以及建立索拉非尼耐药的HCC细胞系显示，NCOA5升高与对索拉非尼（一种常见的HCC化疗药物）的耐药性相关。从机制上讲，NCOA5似乎通过调节谷胱甘肽过氧化物酶4（GPX4）水平来抑制HCC细胞中的铁死亡。敲低NCOA5可使耐药细胞系对索拉非尼敏感，并通过降低GPX4表达诱导铁死亡。此外，NCOA5对GPX4的调节是通过转录因子MYC介导的。体内研究进一步证实，靶向NCOA5通过促进铁死亡增强了索拉非尼在耐药HCC模型中的疗效。总的来说，这些发现强调了NCOA5作为克服HCC耐药性的治疗靶点的潜力，为其在调节治疗反应和患者预后中的作用提供了见解。
