Fuzheng Xiaoyan Granules ameliorate cancer-related fatigue during breast cancer chemotherapy by regulating the AKT1/BAD/BCL-2 pathway

doi:10.12122/j.issn.1673-4254.2025.12.12

Abstract

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

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.

Figures/Tables 16

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

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

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

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

Fig.2 Component-target-disease network diagram.

Fig.3 Protein-protein interaction network.

Fig.4 Potential targets diagram.

Fig.5 Core targets diagram.

Fig.6 GO and KEGG analysis.

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

Fig.8 Results of molecular dynamics simulation.

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.

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.

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.

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.

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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