扶正消岩颗粒通过调控AKT1/BAD/BCL-2通路改善乳腺癌化疗期癌因性疲乏

doi:10.12122/j.issn.1673-4254.2025.12.12

摘要/Abstract

摘要：

目的基于扶正祛邪理论探究扶正消岩颗粒对乳腺癌化疗期癌因性疲乏（CRF）的治疗效果及作用机制。方法将90例正虚毒瘀型乳腺癌 CRF 患者随机分为对照组（化疗及对症治疗）、研究组（加服扶正消岩颗粒），45例/组。比较两组Piper 疲乏量表（PFS）、Karnofsky 功能状态（KPS）量表及中医证候评分。利用多数据库分析药物活性成分、靶点及疾病相关靶点，构建 PPI 网络并富集分析，通过分子对接和动力学模拟研究主要成分槲皮素与AKT1等核心靶点作用情况。构建乳腺癌 CRF 小鼠模型，设正常对照组、模型组和扶正消岩颗粒灌胃治疗组，检测不同组小鼠运动功能改变、腓肠肌组织凋亡相关蛋白AKT1、p-AKT1、BCL-2、BAD表达及血清 IL-6、IL-1β水平。结果研究组治疗后PFS、KPS及中医证候评分结果均优于治疗前和对照组（P<0.05）；筛选出57个药物与疾病交集靶标，确定5个关键靶点，发现主要成分槲皮素与AKT1等核心靶点强结合，并可能通过凋亡通路发挥作用；扶正消岩颗粒可改善小鼠运动能力，逆转腓肠肌凋亡蛋白表达异常，降低血清IL-6、IL-1β水平（P<0.05）。结论扶正消岩颗粒可缓解乳腺癌患者化疗期癌因性疲乏，改善中医证候和生活质量，改善疲乏模型小鼠体能，可能通过调控 AKT1/BAD/BCL-2通路抑制骨骼肌凋亡，下调 IL-6、IL-1β水平发挥作用。

关键词: 扶正消岩颗粒, 乳腺癌, 癌因性疲乏, 网络药理学, AKT1/BAD/BCL-2信号通路

Abstract:

Objective To explore the therapeutic mechanism of Fuzheng Xiaoyan (FZXY) Granules for relieving cancer-related fatigue (CRF) during chemotherapy in breast cancer patients based on the traditional Chinese medicine (TCM) theory of "Fuzheng Quxie" (supporting healthy qi and eliminating pathogens). Methods Ninety CRF patients with breast cancer and Zhengxu Duyu syndrome were randomized equally into control group with chemotherapy and symptomatic treatment and study group with additional treatment with FZXY Granules, and their Piper Fatigue Scale (PFS), Karnofsky Performance Status (KPS), and TCM syndrome scores were compared. Network pharmacology analysis was used to identify the active components in FZXY Granules, the drug targets, and disease-related targets. Protein-protein interaction (PPI) network was constructed followed by enrichment analysis. Molecular docking study was conducted to explore the interactions between quercetin and the core targets. In a CRF mouse model bearing breast cancer xenograft, the effects of saline and FZXY Granule gavage were observed by assessing motor function, expressions of AKT1, p-AKT1, BCL-2, and BAD in the gastrocnemius muscle, and serum levels of IL-6 and IL-1β. Results The patients receiving FZXY Granules treatment showed significantly improved PFS, KPS, and TCM syndrome scores compared with the baseline levels and those in the control group (P<0.05). Fifty-seven overlapping drug-disease targets were screened, and 5 core targets were identified. Quercetin exhibited strong binding to AKT1 and acted likely via the apoptosis pathways. In the CRF mouse models, FZXY Granules obviously improved motor function of the mice, reversed abnormal apoptosis-related protein expressions in the gastrocnemius muscle, and reduced serum IL-6 and IL-1β levels. Conclusion FZXY Granules alleviate CRF and improve TCM symptoms and quality of life of breast cancer patients during chemotherapy possibly by suppressing skeletal muscle cell apoptosis via regulating the AKT1/BAD/BCL-2 pathway and reducing IL-6 and IL-1β levels.

Key words: Fuzheng Xiaoyan Granules, breast cancer, cancer-related fatigue, network pharmacology, AKT1/BAD/BCL-2 signaling pathway

孙心悦, 王宽宇, 王钢, 代清泉, 陈静, 孔祥定, 栾佳. 扶正消岩颗粒通过调控AKT1/BAD/BCL-2通路改善乳腺癌化疗期癌因性疲乏[J]. 南方医科大学学报, 2025, 45(12): 2646-2657.

Xinyue SUN, Kuanyu WANG, Gang WANG, Qingquan DAI, Jing CHEN, Xiangding KONG, Jia LUAN. Fuzheng Xiaoyan Granules ameliorate cancer-related fatigue during breast cancer chemotherapy by regulating the AKT1/BAD/BCL-2 pathway[J]. Journal of Southern Medical University, 2025, 45(12): 2646-2657.

图/表 16

表1 两组患者治疗前后PFS评分比较

Tab.1 Comparison of PFS scores between the two groups before and after treatment (Mean±SD, n=45)

Group	Behavioral dimension		Emotion dimension		Physical dimension		Cognition dimension
Group	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Control	5.84±0.69	4.88±0.65	5.93±0.84	4.32±1.06	5.17±1.12	4.64±0.54	6.39±1.09	4.29±1.32
Treatment	5.55±0.88	3.14±1.23^a	5.60±0.92	2.77±1.56^a	5.38±0.51	2.96±1.00^a	6.35±0.97	2.87±1.41^a
t	1.754	8.381	1.799	6.617	-1.138	9.894	0.187	4.93
P	0.083	<0.001	0.075	<0.001	0.258	<0.001	0.852	<0.001

表2 两组患者治疗前后KPS评分比较

Tab.2 Comparison of KPS scores between the two groups before and after treatment ［M (P25, P75), n=45］

Group	Before treatment	After treatment	Z	P
Control	70 (60, 80)	80 (70, 80)	-4.849	<0.001
Treatment	70 (70, 80)	80 (80, 90)	-6.474	<0.001
Z	-0.720	-3.499
P	0.471	<0.001

表3 两组患者治疗前后中医证候评分比较

Tab.3 Comparison of TCM Syndrome Scores between the two groups of patients before and after treatment (Mean±SD, n=45)

Group	Tiredness and weakness		Nausea and vomiting		Dizziness and dim vision		Palpitations and insomnia
Group	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Control	2.87±0.50	1.96±0.21	2.80±0.55	1.91±0.36	2.49±0.63	1.84±0.47	1.78±1.08	1.27±0.84
Treatment	2.87±0.46	0.91±0.29^a	2.87±0.46	1.36±0.74^a	2.33±0.64	0.69±0.56^a	1.76±1.00	0.91±0.73^a
Z	-0.339	-8.866	-0.666	-3.846	-1.226	-7.36	-2.40	-2.18
P	0.735	<0.001	0.505	<0.001	0.22	<0.001	0.810	0.029

图1 药物-疾病交集靶点韦恩图

Fig.1 Venn diagram of drug-disease intersecting targets.

图2 成分-靶点-疾病网络图

Fig.2 Component-target-disease network diagram.

图3 PPI图

Fig.3 Protein-protein interaction network.

图4 潜在靶点图

Fig.4 Potential targets diagram.

图5 核心靶点图

Fig.5 Core targets diagram.

图6 GO及KEGG分析

Fig.6 GO and KEGG analysis.

图7 槲皮素与AKT1、EGFR、IL1β、IL6、TP53分子对接示意图

Fig.7 Molecular docking study of binding of quercetin with AKT1 (A), EGFR (B), IL1β (C), IL6 (D) and TP53 (E).

图8 分子动力学模拟结果

Fig.8 Results of molecular dynamics simulation.

图9 各组小鼠强迫游泳实验比较

Fig.9 Performance of the mice in forced swimming test in different groups. A: After successful model establishment; B: After FZXY intervention. *P<0.05, **P<0.01 vs control group; #P<0.05 vs CRF group.

图10 各组小鼠旷场实验、悬尾实验比较

Fig.10 Comparison of open field test and tail suspension test of mice in different groups. **P<0.01, ***P<0.001, ****P<0.0001 vs Control group; #P<0.05,###P<0.001 vs CRF group.

图11 各组小鼠体质量、腓肠肌质量比较

Fig.11 Comparison of body weight and gastrocnemius muscle weight of the mice among the 3 groups. *P<0.05, **P<0.01 vs control group; #P<0.05, ##P<0.01 vs CRF group. Day 1 is defined as the day of doxorubicin injection.

图12 各组血清IL-6、IL-1β水平比较

Fig.12 Comparison of serum IL-6 and IL-1β levels among 3 groups. *P<0.05 vs Control group, #P<0.05 vs CRF group.

图13 各组腓肠肌蛋白表达水平比较

Fig.13 Comparison of protein expression levels in the gastrocnemius muscles of the mice among the 3 groups. *P<0.05, **P<0.01, ***P<0.001 vs Control group; #P<0.05 vs CRF group.

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