Qin Jiayi, Li Zhuan
The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Pharmaceutic Science, Health Science Center, Hunan Normal University, Changsha 410013, China.
Int J Mol Sci. 2025 Apr 17;26(8):3816. doi: 10.3390/ijms26083816.
Cyclin-dependent kinase 1 (CDK1) has emerged as a critical regulator of cell cycle progression, yet its role in liver fibrosis-associated hepatocellular carcinoma (LF-HCC) remains underexplored. This study aimed to systematically evaluate CDK1's prognostic significance, immune regulatory functions, and therapeutic potential in LF-HCC pathogenesis. Integrated bioinformatics approaches were applied to multi-omics datasets from GEO, TCGA, and TIMER databases. Differentially expressed genes were identified through enrichment analysis and protein-protein interaction networks. Survival outcomes were assessed via Kaplan-Meier analysis, while immune cell infiltration patterns were quantified using CIBERSORT. Molecular docking simulations evaluated CDK1's binding affinity with pharmacologically active compounds (alvocidib, seliciclib, alsterpaullone) using AutoDock Vina. CDK1 demonstrated significant overexpression in LF-HCC tissues compared to normal controls ( < 0.001). Elevated CDK1 expression correlated with reduced overall survival (HR = 2.41, 95% CI:1.78-3.26, = 0.003) and advanced tumor staging ( = 0.007). Immune profiling revealed strong associations between CDK1 levels and immunosuppressive cell infiltration, particularly regulatory T cells (r = 0.63, = 0.001) and myeloid-derived suppressor cells (r = 0.58, = 0.004). Molecular docking confirmed high-affinity binding of CDK1 to kinase inhibitors through conserved hydrogen-bond interactions (binding energy ≤ -8.5 kcal/mol), with alvocidib showing optimal binding stability. This multimodal analysis establishes CDK1 as both a prognostic biomarker and immunomodulatory regulator in LF-HCC pathogenesis. The enzyme's dual role in driving tumor progression and reshaping the immune microenvironment positions it as a promising therapeutic target. Computational validation of CDK1 inhibitors provides a rational basis for developing precision therapies against LF-HCC, bridging translational gaps between biomarker discovery and clinical application.
细胞周期蛋白依赖性激酶1（CDK1）已成为细胞周期进程的关键调节因子，但其在肝纤维化相关肝细胞癌（LF-HCC）中的作用仍未得到充分探索。本研究旨在系统评估CDK1在LF-HCC发病机制中的预后意义、免疫调节功能和治疗潜力。综合生物信息学方法应用于来自GEO、TCGA和TIMER数据库的多组学数据集。通过富集分析和蛋白质-蛋白质相互作用网络鉴定差异表达基因。通过Kaplan-Meier分析评估生存结果，同时使用CIBERSORT量化免疫细胞浸润模式。分子对接模拟使用AutoDock Vina评估CDK1与药理活性化合物（阿沃西地、塞利西利布、奥斯特帕隆）的结合亲和力。与正常对照相比，CDK1在LF-HCC组织中显著过表达（<0.001）。CDK1表达升高与总生存期缩短（HR = 2.41，95% CI：1.78-3.26，= 0.003）和肿瘤分期进展（= 0.007）相关。免疫谱分析显示CDK1水平与免疫抑制细胞浸润之间存在密切关联，特别是调节性T细胞（r = 0.63，= 0.001）和骨髓来源的抑制细胞（r = 0.58，= 0.004）。分子对接证实CDK1通过保守的氢键相互作用与激酶抑制剂具有高亲和力结合（结合能≤ -8.5 kcal/mol），阿沃西地显示出最佳的结合稳定性。这种多模式分析确定CDK1在LF-HCC发病机制中既是预后生物标志物又是免疫调节因子。该酶在驱动肿瘤进展和重塑免疫微环境中的双重作用使其成为一个有前景的治疗靶点。CDK1抑制剂的计算验证为开发针对LF-HCC的精准疗法提供了合理依据，弥合了生物标志物发现与临床应用之间的转化差距。
Zotero 插件
