化结消瘤方中的熊果酸通过诱导铜死亡抑制结直肠癌细胞生长

doi:10.12122/j.issn.1673-4254.2026.04.11

南方医科大学学报 ›› 2026, Vol. 46 ›› Issue (4): 825-837.doi: 10.12122/j.issn.1673-4254.2026.04.11

• • 上一篇

化结消瘤方中的熊果酸通过诱导铜死亡抑制结直肠癌细胞生长

金成桓¹^,²(), 洪宗超¹^,²(), 段雪云³, 范恒⁴, 杨晶鑫¹^,², 秦佳美², 邹丽艳², 覃孟渊⁵

^1.湖北民族大学武陵山中药材检验检测中心，湖北恩施 445000
^2.湖北民族大学医学部，恩施 445000
^3.湖北省中医院，武汉 430065
^4.华中科技大学同济医学院附属协和医院，湖北恩施 430022
^5.利川市民族中医院，湖北恩施 445000

收稿日期:2025-09-25 出版日期:2026-04-20 发布日期:2026-04-24
通讯作者: 洪宗超 E-mail:1659939107@qq.com;1286069643@qq.com
作者简介:金成桓，在读硕士研究生，E-mail: 1659939107@qq.com
基金资助:
国家自然科学基金(82505189);国家重点研发计划中医药现代化重点专项(2025YFC3508502);湖北省自然科学基金(2023AFD067);湖北省教育厅科学研究计划青年人才项目(Q20231904)

Ursolic acid in Huajie Xiaoliu Formula inhibits colorectal cancer cell growth by inducing cuproptosis

Chenghuan JIN¹^,²(), Zongchao HONG¹^,²(), Xueyun DUAN³, Heng FAN⁴, Jingxing YANG¹^,², Jiamei QIN², Liyan ZOU², Mengyuan QIN⁵

^1.Chinese Medicinal Materials Products Quality Supervision and Inspection Center in Wuling Mountainous Area, Hubei Minzu University, Enshi 445000, China
^2.Health Science Center, Hubei Minzu University, Enshi 445000, China
^3.Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430065, China
^4.Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
^5.Lichuan Municipal Hospital of Traditional Chinese Medicine, Enshi 445000, China

Received:2025-09-25 Online:2026-04-20 Published:2026-04-24
Contact: Zongchao HONG E-mail:1659939107@qq.com;1286069643@qq.com
Supported by:
National Natural Science Foundation of China(82505189)

摘要/Abstract

摘要：

目的探讨化结消瘤方（HJF）及其活性成分熊果酸（Ursolic acid）通过铜死亡抗结直肠癌（CRC）的分子机制。方法采用蛋白质组学分析化结消瘤方对结直肠癌蛋白表达谱的影响；血清药物化学探索化结消瘤方抗结直肠癌的潜在活性物质；通过网络药理学和分子对接预测熊果酸与铜死亡相关靶点的相互作用；采用MTT、划痕、克隆形成、Western blotting等细胞生物学实验验证熊果酸对HCT-116和LOVO细胞增殖、迁移及铁氧还蛋白1（FDX1）、溶质载体家族31成员1（SLC31A1）、二氢硫辛酸转乙酰基酶（DLAT）、谷胱甘肽（GSH）、丙二醛（MDA）、丙酮酸、Cu²⁺等铜死亡相关指标的影响。结果化结消瘤方调控628个差异表达蛋白，涉及炎症、免疫、代谢等通路；熊果酸为其主要入血成分，与铜死亡关键蛋白FDX1具有强结合潜力（对接分数106.813），可抑制结肠癌细胞增殖与迁移，诱导Cu²⁺（P<0.05）、MDA（P<0.05）和丙酮酸（P<0.01）积累，降低GSH水平（P<0.01），抑制DLAT表达并上调FDX1和SLC31A1表达。结论熊果酸作为化结消瘤方发挥抗结直肠癌作用的关键活性成分之一，通过靶向FDX1在结直肠癌细胞中诱导铜死亡，从而发挥抗肿瘤作用。

关键词: 熊果酸, 结直肠癌, 铜死亡, 化结消瘤方

Abstract:

Objective To investigate the molecular mechanism by which Huajie Xiaoliu Formula (HJF) and its active component ursolic acid inhibit colorectal cancer (CRC) cell growth. Methods Proteomics was used to analyze the effect of HJF on protein expression profile in CRC xenografts from tumor-bearing nude mice. Serum pharmacochemistry was used to identify the potential active components of HJF. Network pharmacology and molecular docking were employed to predict the interaction between ursolic acid and cuproptosis-related targets. Cellular assays including MTT, wound healing, colony formation, and Western blotting were used to validate the effects of ursolic acid on proliferation, migration, and cuproptosis-related indicators (FDX1, SLC31A1, DLAT, GSH, MDA, pyruvic acid, and Cu²⁺) in HCT-116 and LoVo cells. Results HJF regulated 628 differentially expressed proteins in CRC, involving pathways related to inflammation, immunity, and metabolism. Ursolic acid was identified as a major blood component of HJF and exhibited a strong binding affinity with the key cuproptosis protein FDX1 (LiDock Score106.813). In HCT-116 and LoVo cells, ursolic acid significantly inhibited cell proliferation and migration, induced intracellular accumulation of Cu²⁺, MDA and pyruvic acid, reduced GSH levels, inhibited cellular DLAT expression, and up-regulated the expressions of FDX1 and SLC31A1. Conclusion As one of the key active components in the HJF, ursolic acid inhibits CRC cell growth by inducing cuproptosis via targeting FDX1.

Key words: ursolic acid, colorectal cancer, cuproptosis, Huajie Xiaoliu Formula

金成桓, 洪宗超, 段雪云, 范恒, 杨晶鑫, 秦佳美, 邹丽艳, 覃孟渊. 化结消瘤方中的熊果酸通过诱导铜死亡抑制结直肠癌细胞生长[J]. 南方医科大学学报, 2026, 46(4): 825-837.

Chenghuan JIN, Zongchao HONG, Xueyun DUAN, Heng FAN, Jingxing YANG, Jiamei QIN, Liyan ZOU, Mengyuan QIN. Ursolic acid in Huajie Xiaoliu Formula inhibits colorectal cancer cell growth by inducing cuproptosis[J]. Journal of Southern Medical University, 2026, 46(4): 825-837.

图/表 12

图1 化结消瘤方抗结直肠癌的蛋白组学研究

Fig.1 Proteomic study of HJF in treatment for CRC. A: Volcano plot for high-throughput detection of protein expression, including 334 downregulated proteins (blue) and 294 upregulated proteins (red); B: Partial results of GO enrichment of the differentially expressed proteins. C: Partial results of KEGG enrichment of the differentially expressed proteins. D: Intersection diagram of the differentially expressed proteins and cuproptosis-related proteins detected by proteomics, showing a total of 100 proteins related to cuproptosis.

图2 铜死亡相关差异表达蛋白及LC-MS/MS分析谱图

Fig.2 Differential expression of cuproptosis-related proteins and LC-MS/MS analysis spectrum. A: Heat map of differential expression of 19 cuproptosis-related proteins. B: Display of interactions between 19 cuproptosis-related proteins. C: TIC spectrum of LC-MS/MS in positive ion mode (from top to bottom: LC-MS/MS analysis results of blank serum, drug-containing serum, and HJF). D: TIC spectrum of LC-MS/MS in negative ion mode (from top to bottom: LC-MS/MS analysis results of blank serum, drug-containing serum, and HJF).

表1 化结消瘤方中的20个入血成分

Tab.1 Identification of 20 metabolites of Huajie Xiaoliu Formula （HJF） in plasma by LC- MS analysis

No.	RT (min)	Name	Formula	Theoretical molecular weight	Measured molecular weight
1	3.41	Protocatechuic acid	C₇H₆O₄	154.0266	[M-H]^-153.0170
2	4.71	Deacetylasperulosidic acid methyl ester	C₁₇H₂₄O₁₁	404.1319	[M+Na]⁺ 427.1221 [M-H]^-403.1210
3	6.36	Chlorogenic acid	C₁₆H₁₈O₉	354.0951	[M+H]⁺ 355.1083 [M-H]^-353.0847
4	6.88	Asperulosidic acid	C₁₈H₂₄O₁₂	432.1268	[M+Na]⁺ 455.1141 [M-H]^-431.1172
5	9.98	Ferulic acid	C₁₀H₁₀O₄	194.0579	[M+H]⁺ 195.0636 [M-H]^- 193.0475
6	10.86	Calycosin-7-O-β-D-glucoside	C₂₂H₂₂O₁₀	446.1213	[M+H]⁺ 447.1302 [M-H]^- 445.1112
7	11.64	Scutellarin	C₂₁H₁₈O₁₂	462.0798	[M+H]⁺ 463.0850 [M-H]^- 461.0727
8	12.07	Rutoside	C₂₇H₃₀O₁₆	610.1534	[M+H]⁺ 611.1584 [M-H]^-609.1432
9	13.00	Hesperidin	C₂₈H₃₄O₁₅	610.1898	[M+H]⁺ 611.1989 [M-H]^- 609.1786
10	13.78	Isoliquiritin	C₂₁H₂₂O₉	418.1264	[M+H]⁺ 419.1331 [M-H]^- 417.1166
11	13.96	Ononin	C₂₂H₂₂O₉	430.1264	[M+H]⁺ 431.1321 [M-H]^- 429.1211
12	15.26	10-Deacetylbaccatin III	C₂₉H₃₆O₁₀	544.2308	[M+H]⁺ 545.2370 [M-H]^- 543.2204
13	15.41	Calycosin	C₁₆H₁₂O₅	284.0685	[M+H]⁺ 285.0760 [M-H]^- 283.0602
14	18.62	Formononetin	C₁₆H₁₂O₄	268.0736	[M+H]⁺ 269.0824 [M-H]^-267.0657
15	19.83	Heterophyllin B	C₄₀H₅₈N₈O₈	778.4378	[M+H]⁺779.4432 [M-H]^-777.4281
16	20.22	6-Gingerol	C₁₇H₂₆O₄	294.1831	[M+Na]⁺ 317.1717
17	23.40	Paclitaxel	C₄₇H₅₁NO₁₄	853.3310	[M+H]⁺ 854.3370 [M-H]^-852.3248
18	24.21	Glycyrrhizic acid	C₄₂H₆₂O₁₆	822.4038	[M+H]⁺ 823.4129 [M-H]^-821.3976
19	33.88	Pachymic acid	C₃₃H₅₂O₅	528.3815	[M+H]⁺ 529.3902 [M-H]^- 527.3729
20	35.03	Ursolic Acid	C₃₀H₄₈O₃	456.3603	[M+H]⁺ 457.3694 [M-H]^-455.3524

图3 化结消瘤方的网络药理学分析

Fig.3 Network pharmacology analysis related to HJF. A: Network construction results of HJFTCM-Chemical Components. B: Network construction results of HJF-TCM-Enter blood chemical components. C: Display of Chinese herbal medicines containing ursolic acid. D: Chemical structure of ursolic acid.

图4 公共数据集分析

Fig.4 Public data analysis. A: Volcano map of differential gene expression in primary colon cancer and normal tissue. B: Volcano map of differential gene expression in metastatic colon cancer and normal tissue. C: Statistical chart of differentially expressed genes in colon cancer. D: There are a total of 1309 differentially expressed genes in primary colon cancer and metastatic colon cancer. E: Diffusion mapping of 1309 differentially expressed genes in normal tissues, primary colon cancer, and metastatic colon cancer. F: Expression heatmap of 1309 genes in normal tissues, primary colon cancer, and metastatic colon cancer.

图5 公共数据集中铜死亡相关基因的筛选

Fig.5 Identification of cuproptosis-related genes in public data. A: Among the 1309 differentially expressed genes, 9 genes are associated with cuprotosis. B: Correlation heatmap of 9 cuprotosis-related genes. C: Co-expression networks of 9 cuprotosis-related genes. D: Patients with low expression of CDKN2A gene are more likely to have longer overall survival. E: Patients with high expression of DNA2 gene are more likely to have longer overall survival. F: Patients with high expression of FDX1 gene are more likely to have longer overall survival.

图6 基于GEPIA2验证分析结直肠癌中的基因表达差异

Fig.6 GEPIA2 analysis of genes that are significantly differentially expressed in CRC. Red color represents tumor tissue, and green color represents normal tissue.

图7 熊果酸的网络药理学分析

Fig.7 Network pharmacology analysis of ursolic acid. A: PPI network of 241 predicted targets of ursolic acid. B: 5 clusters analyzed by MCODE. C: PPI network of 54 genes in 5 clusters. D: GO analysis results of 54 genes. E: KEGG analysis results of 54 genes.

表2 预测靶点PPI网络的MCODE分析结果

Tab.2 Clusters of the predicted target in the PPI network

Gene cluster	Score	Node	Edge	Genes
Cluster 1	7.455	12	41	ABCB1, BTK, ITK, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PRKACA, PTPN11, SLC2A1, STAT3, TLR4
Cluster 2	7.13	24	82	APEX1, AR, C5AR1, CDK1, CHUK, EIF2AK2, FPR1, GRB2, HDAC4, HDAC5, HSP90AB1, KDM1A, MDM2, MTOR, NFE2L2, NFKB1, NOS2, NR3C1, PDGFRA, PRKCD, RAC1, S100A12, SERPINE1, SOD2
Cluster 3	3.8	11	19	CALM3, ENG, HIF1A, ITGB1, PRKCA, PSMB9, RPS6KA1, SPOP, TGFBR2, USP7, YAP1
Cluster 4	3.333	4	5	CCR1, FPR2, RGS18, TLR8
Cluster 5	3	3	3	CUL1, FBXW7, PSMB1

图8 熊果酸与各蛋白的分子对接结果

Fig.8 Molecular docking between ursolic acid and its targets. A: BOP1-ursolic acid; B: DNA2-ursolic acid; C: FDX1-ursolic acid; D: PPAT-ursolic acid; E: SLC2A1-ursolic acid; F: SLC7A11-ursolic acid.

表3 熊果酸与各靶点分子对接的得分

Tab.3 Scoring of ursolic acid-protein binding

Target	PDB code	LiDock Score
BOP1	4qi1	78.5132
CDKN2A	7ozt	N/A
DNA2	5ean	56.8153
FANCI	6tnf	N/A
FDX1	3n9y	106.813
HSPD1	6mrc	N/A
PPAT	4nat	58.2893
SERPINE1	3cvm	N/A
SLC2A1	4pyp	113.927
SLC7A11	7ccs	102.503
SLC31A1	2ls2	N/A

图9 熊果酸对结直肠癌细胞铜死亡的调控作用

Fig.9 Regulatory effect of ursolic acid on cuproptosis in CRC. A: Ursolic acid significantly inhibits the growth of HCT-116 and LoVo cells. B: Ursolic acid reduces migration of colon cancer cells. C: Ursolic acid inhibits clone formation of colon cancer cells. D-G: Changes in pyruvate (D), Cu2+ (E), GSH (F), and MDA (G) before and after ursolic acid intervention. H: Ursolic acid upregulates the expression of SLC31A1 and FDX1. I: Ursolic acid inhibits the expression of DLAT. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

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化结消瘤方中的熊果酸通过诱导铜死亡抑制结直肠癌细胞生长

Ursolic acid in Huajie Xiaoliu Formula inhibits colorectal cancer cell growth by inducing cuproptosis

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