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

Yuan Zhang,1,2 Linjie Ruan,1,2 Xin Li,1,2 Waimei Si,1,2 Peiwen Yang,1,2 He Ba,1,2 Zhen Chen1,2 1Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Zhen Chen, Department of Integrative Oncology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Email [email protected]: 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.Keywords: Traditional Chinese Medicine, integrated pharmacology, macrophage polarization, molecular mechanism, Pancreatic Cancer