Qi Zhuoran, Luo Jie, Liu Wenfeng, Xu Ye, Ma Yifan, Hu Sunkuan, Shen Xizhong, Du Xiaojing, Xiang Wei
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Huashan Hospital, Fudan University, Shanghai, China.
J Biol Chem. 2025 Apr 30;301(6):108558. doi: 10.1016/j.jbc.2025.108558.
Hepatocellular carcinoma tumor-repopulating cells (HCC-TRCs) drive disease progression, yet their purine metabolism mechanisms remain poorly understood. This study revealed that the stemness index, strongly linked to poor HCC prognosis, exhibited a robust positive correlation with purine metabolism through single-sample gene set enrichment analysis. Integrated drug screening across CTRP, GDSC, and PRISM databases identified alisertib, an aurora kinase A (AURKA) inhibitor, as a potent agent targeting stemness. Using fibrin gel-based 3D-cultured HCC-TRCs, mechanistic studies demonstrated that alisertib suppresses xanthine and hypoxanthine production by inhibiting the AURKA-AKT signaling axis. This disruption markedly impaired tumor spheroid formation, migration, and invasion in vitro, while significantly suppressed tumor growth in vivo, which could be rescued by the AKT agonist SC79. Our findings revealed a novel therapeutic strategy targeting purine metabolism through AURKA-AKT axis inhibition, effectively eliminating HCC-TRCs.
肝细胞癌肿瘤再增殖细胞（HCC-TRCs）驱动疾病进展，但其嘌呤代谢机制仍知之甚少。本研究通过单样本基因集富集分析表明，与肝癌预后不良密切相关的干性指数与嘌呤代谢呈显著正相关。通过整合CTRP、GDSC和PRISM数据库进行药物筛选，发现极光激酶A（AURKA）抑制剂阿利西尤单抗是一种靶向干性的有效药物。利用基于纤维蛋白凝胶的3D培养HCC-TRCs进行的机制研究表明，阿利西尤单抗通过抑制AURKA-AKT信号轴来抑制黄嘌呤和次黄嘌呤的产生。这种干扰显著损害了肿瘤球体在体外的形成、迁移和侵袭，同时在体内显著抑制了肿瘤生长，而AKT激动剂SC79可以挽救这种抑制作用。我们的研究结果揭示了一种通过抑制AURKA-AKT轴靶向嘌呤代谢的新治疗策略，可有效消除HCC-TRCs。
