Fan Lei, Liu Yiqian, Cai Yucheng, Sun Xinnan, Li Jiaxuan, Xu Yiyang, Sun Changchun, Cui Shiyun
Department of General Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing, Jiangsu, P. R. China.
Department of General Surgery, Jiangsu Province Academy of Traditional Chinese Medicine Nanjing, Jiangsu, P. R. China.
Am J Cancer Res. 2025 Aug 25;15(8):3693-3711. doi: 10.62347/JTQO8098. eCollection 2025.
This study aims to explore Aurora-A's role in regulating immune escape of hepatocellular carcinoma (HCC). We performed non-targeted metabolomics analysis and analyzed the impact of Aurora-A inhibitor Alisertib on anti-PD-1 therapy efficacy on xenograft tumors and co-culture models of CD8 T cells and HCC cells. We determined reactive oxygen species (ROS) and malondialdehyde (MDA) production in HCC cells to evaluate lipid peroxidation. Confocal images of endoplasmic reticulum (ER) and mitochondria in HCC cells were taken to assess the role of Aurora-A and dynamin-related protein 1 (Drp-1) on mitochondria-associated endoplasmic reticulum membranes (MAMs) formation. The results showed that Aurora-A was upregulated in HCC cells and its knockdown significantly augmented phosphatidylethanolamine (PE) production while having no effect on phosphatidylserine decarboxylase (PSD). Further, Aurora-A inhibitor Alisertib enhanced the sensibility of HCC cells to anti-PD-1 therapy and CD45CD8 T cell infiltration in HCC tumors. To conclude, our work revealed that Aurora-A dysregulated PS/PE metabolism via facilitating Drp1-Ser616 phosphorylation to disrupt MAMs formation, resulting in suppressed ferroptosis in HCC cells to reduce their sensitivity to anti-PD-1.
本研究旨在探讨Aurora-A在调节肝细胞癌（HCC）免疫逃逸中的作用。我们进行了非靶向代谢组学分析，并分析了Aurora-A抑制剂Alisertib对异种移植肿瘤以及CD8 T细胞与HCC细胞共培养模型中抗PD-1治疗疗效的影响。我们测定了HCC细胞中活性氧（ROS）和丙二醛（MDA）的产生，以评估脂质过氧化。拍摄了HCC细胞内质网（ER）和线粒体的共聚焦图像，以评估Aurora-A和动力蛋白相关蛋白1（Drp-1）在线粒体相关内质网膜（MAMs）形成中的作用。结果显示，Aurora-A在HCC细胞中上调，其敲低显著增加了磷脂酰乙醇胺（PE）的产生，而对磷脂酰丝氨酸脱羧酶（PSD）没有影响。此外，Aurora-A抑制剂Alisertib增强了HCC细胞对抗PD-1治疗的敏感性以及HCC肿瘤中CD45CD8 T细胞的浸润。总之，我们的研究表明，Aurora-A通过促进Drp1-Ser616磷酸化来破坏MAMs形成，从而失调PS/PE代谢，导致HCC细胞中的铁死亡受到抑制，降低其对抗PD-1的敏感性。
