Guo Jiageng, Yan Lijiao, Yang Qi, Li Huaying, Tian Yu, Yang Jieyi, Xie Jinling, Zhang Fan, Hao Erwei
Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning 530000, China.
Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530000, China.
Pharmaceuticals (Basel). 2025 Aug 14;18(8):1205. doi: 10.3390/ph18081205.
Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide. Its high recurrence rate and limited treatment options underscore the urgent need for the development of new and highly effective drugs. : This study systematically explores the molecular mechanism of cinnamic acid against hepatocellular carcinoma through integrated machine learning prediction, network pharmacological analysis and in vitro experimental verification. : The prediction of anti-tumor activity based on the random forest model showed that cinnamic acid has significant anti-tumor potential (probability = 0.69). Network pharmacology screened 185 intersection targets of cinnamic acid and liver cancer, of which 39 core targets (such as PIK3R1, AKT1, MAPK1) were identified as key regulatory hubs through protein interaction network and topological analysis. Functional enrichment analysis showed that these targets were mainly enriched in the PI3K/AKT signaling pathway ( = 2.1 × 10), the cancer pathway ( = 3.8 × 10), and apoptosis-related biological processes. Molecular docking validation revealed that the binding energies of cinnamic acid with the 19 core targets were all below -5 kcal/mol, a threshold indicating strong binding affinity in molecular docking. The binding modes to PIK3R1 (-5.4 kcal/mol) and AKT1 (-5.1 kcal/mol) stabilized through hydrogen bonding. In vitro, cinnamic acid dose-dependently inhibited Hep3B proliferation/migration, induced apoptosis, downregulated PI3K, p-AKT, and Bcl-2, and upregulated Bax and Caspase-3/8. : This study systematically reveals, for the first time, that the multi-target mechanism of cinnamic acid exerts anti-hepatic cancer effects by targeting the PI3K/AKT signaling pathway, supporting its potential as a natural anti-tumor drug.
肝细胞癌是全球癌症相关死亡的主要原因之一。其高复发率和有限的治疗选择凸显了开发新型高效药物的迫切需求。本研究通过集成机器学习预测、网络药理学分析和体外实验验证，系统地探索了肉桂酸抗肝细胞癌的分子机制。基于随机森林模型的抗肿瘤活性预测表明，肉桂酸具有显著的抗肿瘤潜力（概率=0.69）。网络药理学筛选出肉桂酸与肝癌的185个交集靶点，其中39个核心靶点（如PIK3R1、AKT1、MAPK1）通过蛋白质相互作用网络和拓扑分析被确定为关键调控枢纽。功能富集分析表明，这些靶点主要富集在PI3K/AKT信号通路（=2.1×10）、癌症通路（=3.8×10）和凋亡相关生物学过程中。分子对接验证显示，肉桂酸与19个核心靶点的结合能均低于-5 kcal/mol，这是分子对接中表明强结合亲和力的阈值。与PIK3R1（-5.4 kcal/mol）和AKT1（-5.1 kcal/mol）的结合模式通过氢键稳定。体外实验中，肉桂酸剂量依赖性地抑制Hep3B细胞增殖/迁移，诱导凋亡，下调PI3K、p-AKT和Bcl-2，上调Bax和Caspase-3/8。本研究首次系统揭示了肉桂酸通过靶向PI3K/AKT信号通路发挥抗肝癌作用的多靶点机制，支持其作为天然抗肿瘤药物的潜力。
