目的 探讨蔓荆子黄素改善炎症相关性结直肠癌（colitis-associated colorectal cancer，CAC）的药效作用及作用机制。方法 建立氧化偶氮甲烷（azoxymethane，AOM）/葡聚糖硫酸钠（dextran sulfate sodium，DSS）诱导的CAC小鼠模型，给予蔓荆子黄素干预。通过比较体质量变化、疾病活动指数、结肠肿瘤负荷、荷瘤生存率、脏器指数、病理学改变及血清肝功能指标，分别评价蔓荆子黄素的药效与安全性作用；采用16S rRNA测序分析肠道菌群结构变化；运用蛋白质组学技术筛选差异表达蛋白及关键信号通路；采用Western blotting验证关键蛋白表达；基于TCGA数据库进行Kaplan-Meier生存分析评估靶基因预后价值，并通过分子对接技术预测蔓荆子黄素与靶蛋白的结合模式；通过关联分析揭示肠道菌群与宿主靶点之间的相互作用关系。结果 与模型组比较，蔓荆子黄素显著缓解CAC小鼠体质量下降，改善肠道炎症反应，降低结肠肿瘤体积与肿瘤负荷（P＜0.05），提高荷瘤小鼠生存率。安全性评价显示，各给药组小鼠血清肝功能指标及主要脏器组织形态未见明显毒性改变。16S rRNA测序显示，蔓荆子黄素有效逆转CAC诱导的肠道菌群失衡，显著下调促癌相关菌门梭杆菌门Fusobacteriota和包氏菌门Patesbacteria的相对丰度，同时富集产短链脂肪酸Lachnospiraceae_NK4A136_group和Prevotellaceae_UCG-001抗炎菌属。蛋白质组学分析锁定补体凝血级联通路为核心响应通路，其中微环境重塑相关分子丝氨酸蛋白酶抑制因子1（serine protease inhibitor 1，Serpine1）和免疫识别受体整合素αM（integrin alpha M，Itgam）的表达呈现剂量相关性回调。Western blotting验证显示，与模型组比较，蔓荆子黄素组小鼠结肠组织Itgam和Serpine1蛋白表达显著下调（P＜0.01、0.001），与蛋白质组学趋势一致。联合分析进一步揭示，Lachnospiraceae_NK4A136_group等有益菌丰度与微环境重塑分子Serpine1表达呈显著负相关，而Fusobacteriota等促癌菌丰度与免疫识别受体Itgam表达呈显著正相关。结论 蔓荆子黄素可通过重塑肠道菌群结构，调控补体凝血级联通路的关键分子响应补体凝血级联通路的关键分子响应，进而协同阻断CAC炎癌转化进程。

Objective To investigate the pharmacodynamic effect and mechanism of casticin on improving colitis-associated colorectal cancer (CAC). Methods A CAC mouse model was established using azoxymethane (AOM)/dextran sulfate sodium (DSS) induction, followed by intervention with casticin. Therapeutic efficacy and safety of casticin were evaluated by comparing body weight changes, disease activity index, colonic tumor burden, tumor-bearing survival rates, organ indices, pathological alterations and serum liver function indicators. Intestinal microbiota structural alterations were analyzed using 16S rRNA sequencing. Differentially expressed proteins and key signaling pathways were screened through proteomic techniques. Western blotting was performed to validate key protein expressions. Kaplan-Meier survival analysis based on TCGA database was conducted to evaluate the prognostic value of target genes, and molecular docking was employed to predict the binding modes between casticin and target proteins. The interaction between gut microbiota and host targets was revealed through correlation analysis. Results Compared with model group, casticin significantly alleviated body weight loss in CAC mice, improved intestinal inflammatory responses, reduced colonic tumor volume and tumor burden (P < 0.05), and improved survival rates of tumor-bearing mice. Safety evaluation showed no significant abnormalities in serum liver indicators and histomorphology of major organs in all treatment groups. 16S rRNA sequencing demonstrated that casticin effectively reversed CAC-induced intestinal dysbiosis, significantly downregulated the relative abundance of pro-carcinogenic phyla Fusobacteriota and Patesbacteria, while enriched the anti-inflammatory genera Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001 that produce short-chain fatty acids. Proteomic analysis identified the complement and coagulation cascade pathway as the core responsive pathway, with dose-dependent restoration of microenvironment remodeling-related molecule serine protease inhibitor 1 (Serpine1) and immune recognition receptor integrin alpha M (Itgam) expression. Western blotting validation demonstrated that compared with model group, the protein expression levels of Itgam and Serpine1 in colonic tissues were significantly downregulated in casticin group (P < 0.01, 0.001), consistent with the proteomic trend analysis. Integrated analysis further revealed that the abundance of beneficial bacteria such as Lachnospiraceae_NK4A136_group was significantly negatively correlated with the expression of microenvironment remodeling molecule Serpine1, while the abundance of pro-carcinogenic bacteria such as Fusobacteriota was significantly positively correlated with the expression of immune recognition receptor Itgam. Conclusion Casticin can reshape the intestinal microbiota structure, regulate key molecular responses in the complement and coagulation cascade pathway, thereby synergistically blocking the inflammatory-carcinogenic transformation process of CAC.

R285.5

江西省重点研发计划重点项目（2023QGZDSYS003）；江西省自然科学基金会项目（20232BAB216095，20252BAC240492）；江西省研究生创新专项基金项目（YC2025-S718）；江西中医药大学本科生创新创业计划（S202510412104）