基于网络药理学及分子对接探究郁金治疗胆管癌作用及机制

Exploring the Mechanism of Curcumae Radix in Treating Cholangiocarcinoma Based on Network Pharmacology

摘要: 胆管癌是消化系统侵袭性较强的恶性肿瘤之一，早期浸润与远处转移倾向明显，现有化疗、靶向及免疫治疗仍存在疗效受限与耐药等问题。郁金在临床上具有一定的抗炎、抗肿瘤应用基础，可能通过多成分、多靶点、多通路协同抑制肿瘤增殖、侵袭与转移并促进细胞凋亡，但其针对胆管癌的作用靶点与机制尚缺乏系统阐释。本研究采用网络药理学分析与分子对接技术相结合的策略，系统整合郁金中主要活性成分与胆管癌疾病相关作用靶点，旨在揭示郁金在胆管癌辅助治疗中可能发挥作用的潜在分子作用机制。结果显示，筛选获得郁金潜在活性成分7种；郁金与胆管癌共获得276个交集靶点。基因本体(Gene Ontology, GO)富集分析主要涉及蛋白质磷酸化调控、信号转导、膜相关过程、氧化应激及对异生物刺激反应等生物学条目；京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes, KEGG)通路富集分析提示其主要富集于癌症通路、TNF信号通路、PI3K-Akt信号通路、蛋白聚糖相关通路、AGE-RAGE信号通路等。进一步基于STRING构建蛋白互作网络，并筛选核心靶点，MAPK14、BRAF、MMP2、CDK2、KIT、AR等。分子对接结果显示，关键活性成分(以柚皮素为代表)与上述核心靶点均可自发结合，提示其具有多节点协同调控的潜力。综上，郁金可能通过调控核心靶点，协同影响TNF信号通路、PI3K-Akt信号通路以及MMP2介导的侵袭等相关过程，从而抑制胆管癌进展并为联合标准治疗提供潜在辅助治疗依据。

Abstract: Cholangiocarcinoma (CCA) is one of the most aggressive malignancies of the digestive system, characterized by early local invasion and a strong propensity for distant metastasis. Current therapeutic strategies, including chemotherapy, targeted therapy, and immunotherapy, remain limited by suboptimal efficacy and the development of drug resistance. Curcumae Radix (Yujin) has been clinically used for its anti-inflammatory and antitumor properties and may exert anticancer effects through a multi-component, multi-target, and multi-pathway mode of action; however, its molecular targets and mechanisms in cholangiocarcinoma have not been systematically elucidated. In this study, network pharmacology integrated with molecular docking was applied to identify active constituents of Yujin and cholangiocarcinoma-associated targets, aiming to explore the potential molecular basis of Yujin as an adjuvant therapy for cholangiocarcinoma. The analysis identified seven putative active components and 276 overlapping targets between Yujin and cholangiocarcinoma. Gene Ontology (GO) enrichment indicated significant involvement in biological processes such as regulation of protein phosphorylation, signal transduction, membrane-associated functions, oxidative stress, and responses to xenobiotic stimuli. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the target gene set exhibited significant enrichment in cancer-related pathway networks, primarily encompassing the tumor necrosis factor (TNF) signaling pathway, the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway, proteoglycan metabolism-related pathways, and the advanced glycation end product-receptor for advanced glycation end products (AGE-RAGE) signaling pathway—all of which constitute critical regulatory networks in carcinogenesis. A protein-protein interaction (PPI) network was constructed using STRING, and core targets were further screened, including MAPK14, BRAF, MMP2, CDK2, KIT, and AR. Molecular docking demonstrated that key active constituents, represented by naringenin, could spontaneously bind to these core targets, supporting a potential multi-node synergistic regulatory capacity. Collectively, these findings suggest that Yujin may suppress cholangiocarcinoma progression by modulating core targets and coordinately regulating TNF- and PI3K-Akt-related signaling and MMP2-mediated invasion, thereby providing a theoretical basis for its potential use in combination with standard therapies as an adjuvant treatment.