Modified Sijunzi Decoction Inhibits Pancreatic Cancer Progression and Improves Immune Suppression: Network Pharmacology and Experimental Validation.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-10-02 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S520390

Yuan Zhang, Linjie Ruan, Xin Li, Waimei Si, Peiwen Yang, He Ba, Zhen Chen

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引用次数: 0

Abstract

Purpose: This study aimed to assess the effectiveness of Modified Sijunzi Decoction (MSJZD) in pancreatic cancer (PC) treatment. Molecular mechanisms were elucidated and active ingredients were screened using network pharmacology, RNA sequencing, and in vivo experiments, providing a scientific foundation for the clinical application of MSJZD in PC treatment.

Methods: We established an orthotopic PC mouse model and treated it with different MSJZD concentrations to evaluate its efficacy. Ultra-high-performance liquid chromatography Q-Exactive mass spectrometry was used to identify MSJZD components. Through integrated pharmacology analyses, the active ingredients, core targets, and signaling pathways were determined, and active ingredients targeting the core targets were screened using molecular docking simulations. RNA-sequencing analyses of the molecular mechanism of MSJZD in PC treatment were verified using immunohistochemistry and Western blotting. A multiplex immunofluorescence assay was used to detect macrophage and CD8⁺ T cell infiltration levels.

Results: MSJZD effectively inhibited the growth of orthotopic pancreatic tumors in mice via JAK1-STAT3 pathway and reduced Ki-67 expression, with no discernible toxicity to the liver and kidneys. MSJZD relieved immunosuppression by decreasing M2 macrophage infiltration, increasing CD8⁺ T cell infiltration, and lowering the expression of immunosuppressive cytokines (interleukins 10 and 6). Network pharmacology analysis revealed that EGFR, SRC, AKT1, and STAT3 were the core MSJZD targets in PC treatment. Molecular docking revealed a strong binding affinity between wedelolactone and its core target proteins (EGFR, SRC, AKT1).

Conclusion: MSJZD is a safe and effective decoction for PC that exerts anti-tumor effects by inhibiting JAK1-STAT3 pathway and improving immunosuppressive microenvironment by reducing M2 macrophage infiltration and increasing CD8⁺ T cell infiltration. This study reveals MSJZD therapeutic potential and offers a reference for further research.

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加减四君子汤抑制胰腺癌进展及改善免疫抑制：网络药理学及实验验证。

目的：观察加减四君子汤治疗胰腺癌的临床疗效。通过网络药理学、RNA测序、体内实验等手段，阐明其分子机制，筛选有效成分，为MSJZD治疗PC的临床应用提供科学依据。方法：建立原位PC小鼠模型，用不同浓度的MSJZD治疗，观察其疗效。采用超高效液相色谱- q -质谱法对MSJZD的成分进行鉴定。通过综合药理学分析，确定有效成分、核心靶点和信号通路，并通过分子对接模拟筛选靶向核心靶点的有效成分。采用免疫组织化学和Western blotting对MSJZD治疗PC的分子机制进行rna测序分析。采用多重免疫荧光法检测巨噬细胞和CD8+ T细胞浸润水平。结果：MSJZD通过JAK1-STAT3通路有效抑制小鼠原位胰腺肿瘤生长，降低Ki-67表达，对肝脏和肾脏无明显毒性。MSJZD通过降低M2巨噬细胞浸润，增加CD8+ T细胞浸润，降低免疫抑制因子（白细胞介素10和6）的表达来缓解免疫抑制。网络药理学分析显示，EGFR、SRC、AKT1和STAT3是MSJZD治疗PC的核心靶点。分子对接显示wedelolactone与其核心靶蛋白（EGFR， SRC, AKT1）之间具有很强的结合亲和力。结论：复方白骨参汤是一种安全有效的复方白骨参汤，其作用机制是通过抑制JAK1-STAT3通路，减少M2巨噬细胞浸润，增加CD8+ T细胞浸润，改善免疫抑制微环境，发挥抗肿瘤作用。本研究揭示了MSJZD的治疗潜力，为进一步研究提供参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.