目的 探讨经方薏苡附子败酱散（YYFZBJS）对自发结直肠癌的基因工程小鼠（Villin-CreER^T2Kras^G12D/＋Apc^flox/＋）的抗肿瘤作用机制。方法 Villin-CreER^T2Kras^G12D/＋Apc^flox/＋结直肠癌小鼠随机分为模型组和YYFZBJS低、中、高剂量（3.825、7.650、15.300 g·kg^-1）组，对照组采用野生C57BL／ 6J小鼠。YYFZBJS低、中、高剂量组ig给予相应剂量的YYFZBJS，对照组和模型组ig给予0.9%氯化钠溶液12周。检测小鼠肿瘤形成数目、肿瘤大小和肿瘤负荷量。HE染色观察肿瘤分级，免疫组织化学分析表征肿瘤细胞增殖的蛋白5-溴脱氧尿嘧啶核苷（BrdU）的表达变化。运用中药系统药力学TCMSP平台分析YYFZBJS的主要活性成分，并与结直肠癌靶点取交集，利用STRING数据库和Cytoscape构建蛋白质-蛋白质相互作用（PPI）网络获得核心靶点；采用Metascape数据库对交集靶点进行基因本体（GO）注释及京都基因与基因组百科全书（KEGG）通路富集分析，Cytoscape构建“药物-化合物-靶点”网络图，利用AutoDock Tools对关键活性成分和核心靶点进行分子对接。Western blotting检测肠道肿瘤组织中吲哚胺-2,3-双加氧酶1（IDO1）/芳香烃受体（AhR）/β-连环蛋白（β-catenin）途径蛋白表达水平。结果 与对照组相比，模型组100%的小鼠结肠中出现肿瘤，主要为高级别上皮内瘤变。与模型组相比，YYFZBJS低、中、高剂量组小鼠的毛色、生存状态均有所改善，肿瘤数量分别为7.88±2.00（YYFZBJS低剂量组）、6.13±2.17（YYFZBJS中剂量组）和3.13±1.55（YYFZBJS高剂量组），差异具有统计学意义（P＜0.01）。相较于模型组小鼠，YYFZBJS低、中、高剂量组的肿瘤组织中BrdU表达明显降低（P＜0.05）。网络药理学结果显示YYFZBJS与结直肠癌共有靶点183个，包含IDO1、AhR、β-catenin等，涉及癌症途径、色氨酸代谢通路等。与模型组小鼠相比，YYFZBJS高剂量组的肠道肿瘤组织的IDO1、AhR和β-catenin蛋白的表达显著下调（P＜0.01）。结论 YYFZBJS能减缓大肠肿瘤的发展进程，降低肿瘤的恶性分化程度，其作用机制可能是通过调节色氨酸介导的IDO1/AhR/β-catenin途径有效抑制自发结直肠癌的发生。

Objective To investigate the effect of Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) on genetically engineered mice with spontaneous colorectal cancer (Villin-CreER^T2Kras^G12D/＋Apc^flox/＋). Methods Villin-CreER^T2Kras^G12D/＋Apc^flox/＋ colorectal cancer mice were randomly assigned to the model group, YYFZBJS (3.825, 7.650, 15.300 g·kg^-1) dose groups and the wild-type C57BL/6J mice served as the blank control group. The traditional Chinese medicine group was administered YYFZBJS via gavage, while the control and model groups received normal saline gavage for a duration of 12 weeks. Tumor formation, tumor size, and tumor load were subsequently assessed. HE staining was used to observe the tumor grade, and immunohistochemical analysis was performed to characterize the expression of the protein 5-bromo-2'-deoxyuridine (BrdU), which characterizes the proliferation of tumor cells. The principal bioactive constituents of YYFZBJS were identified utilizing the TCMSP analysis platform and subsequently cross-referenced with colorectal cancer-associated targets. Core targets were elucidated through the construction of a protein-protein interaction (PPI) network, employing the STRING database in conjunction with Cytoscape software. Further, gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for the intersection targets were performed using the Metascape database. Cytoscape was utilized to construct the "drug-compound-target" network diagram, while AutoDock Tools facilitated the molecular docking analysis between key active ingredients and core targets. The expression levels of proteins involved in the IDO1/AhR/β-catenin pathway in intestinal tumor tissues were subsequently assessed using Western blotting. Results In comparison to the normal control group, 100% of the mice in the model group developed colon tumors, predominantly high-grade intraepithelial neoplasia. Relative to the model group, the YYFZBJS intervention group exhibited improvements in hair color and survival status. The tumor counts in the intervention groups were 7.88±2.00 (low dose), 6.13±2.17 (medium dose), and 3.13±1.55 (high dose), respectively, with statistically significant differences (P < 0.01). Additionally, the expression of BrdU in tumor tissues was significantly reduced in the Chinese medicine intervention group compared to the model group (P < 0.05). The network pharmacological analysis revealed that YYFZBJS shares 183 common targets with colorectal cancer, including IDO1, AhR, and β- catenin, which are implicated in both cancer pathways and the tryptophan metabolic pathway. In comparison to the model group, the expression levels of IDO1, AhR, and β-catenin proteins in the intestinal tumor tissues of the YYFZBJS high-dose group were significantly down-regulated (P < 0.01). Conclusion YYFZBJS has been demonstrated to decelerate the progression of colorectal tumors and reduce the degree of malignant differentiation of tumors. The underlying mechanism of action is posited to involve the regulation of the IDO1/AhR/β-catenin pathway, mediated by tryptophan, thereby effectively inhibiting the occurrence of spontaneous colorectal cancer.

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国家自然科学基金资助项目（82204887）;上海交大医工交叉项目（YG2022QN082）;上海市科委生药支撑项目（23S21901200）;河南省科技厅科技攻关项目（242102310493）;河南省科技研发计划联合基金项目（242301420116）;河南省中医药科学研究专项课题（2024ZY2145）