目的 基于网络药理学、分子对接及体外实验探讨二氢杨梅素通过下调磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（Akt）信号通路治疗胰腺癌的作用机制。方法 运用网络药理学筛选二氢杨梅素与胰腺癌的共同作用靶点，构建蛋白质相互作用（PPI）网络，进行基因本体（GO）功能和京都基因与基因组百科全书（KEGG）通路富集分析，并进行分子对接验证。采用CCK-8、克隆形成、划痕、Transwell及Annexin V-FITC/PI双染实验分别检测二氢杨梅素对胰腺癌细胞增殖、迁移、侵袭和凋亡的影响；Western blotting检测PI3K/Akt通路中PI3K、p-PI3K、Akt、p-Akt蛋白的表达。结果 共获得89个二氢杨梅素治疗胰腺癌的候选靶点，其中Akt1、低氧诱导因子-1A（HIF-1A）、B细胞淋巴瘤/白血病-2（Bcl-2）、胱天蛋白酶3（CASP3）等为前10位核心靶点。GO和KEGG分析提示二氢杨梅素可能通过胰腺癌通路、PI3K/Akt信号通路及细胞凋亡等过程发挥作用。分子对接显示二氢杨梅素与核心靶点的结合能均小于−6.0 kcal/mol。体外实验结果显示二氢杨梅素可显著抑制胰腺癌细胞增殖、迁移和侵袭，并促进细胞凋亡，同时下调p-PI3K、p-Akt蛋白表达。结论 二氢杨梅素通过多靶点、多通路抑制胰腺癌细胞增殖、迁移、侵袭并诱导凋亡，其机制可能与抑制PI3K/Akt信号通路相关。

Objective To investigate the mechanism by which dihydromyricetin treats pancreatic cancer through downregulation of the PI3K/Akt signaling pathway, based on network pharmacology, molecular docking, and in vitro experiments. Methods Network pharmacology was used to screen the co-action targets of dihydromyricetin and pancreatic cancer, construct a PPI network, conduct GO function and KEGG pathway enrichment analysis, and perform molecular docking verification. The effects of dihydromyricetin on the proliferation, migration, invasion and apoptosis of pancreatic cancer cells were detected by CCK-8, clone formation, scratch, Transwell and Annexin V-FITC/PI double staining assay, respectively. Western blotting was used to detect the expression of PI3K, p-PI3K, Akt, and p-Akt proteins in the PI3K/Akt pathway. Results A total of 89 potential targets of dihydromyricetin against pancreatic cancer were identified, with Akt1, HIF-1A, Bcl-2, CASP3 among the top 10 core targets. GO and KEGG analyses indicated that dihydromyricetin may exert its effects through pathways such as pancreatic cancer, PI3K/Akt signaling, and apoptosis. Molecular docking demonstrated that the binding energies between dihydromyricetin and the core targets were all below −6.0 kcal/mol, indicating stable binding. In vitro experiments confirmed that dihydromyricetin significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells, promoted apoptosis, and downregulated the expression of p-PI3K and p-Akt proteins. Conclusion Dihydromyricetin inhibits proliferation, migration, and invasion while inducing apoptosis in pancreatic cancer cells through multi-target and multi-pathway mechanisms, which may be associated with the suppression of the PI3K/Akt signaling pathway.

R286.7

福建省自然科学基金项目（2022J01392）；福建省中青年教师教育科研项目（JAT210791）；福建卫生职业技术学院青年科研项目（MWY2023-1-03）