Table_2_System Pharmacology-Based Strategy to Decode the Synergistic Mechanism of Zhi-zhu Wan for Functional Dyspepsia.DOCX

Functional dyspepsia (FD) is a widely prevalent gastrointestinal disorder throughout the world, whereas the efficacy of current treatment in the Western countries is limited. As the symptom is equivalent to the traditional Chinese medicine (TCM) term “stuffiness and fullness,” FD can be treated with Zhi-zhu Wan (ZZW) which is a kind of Chinese patent medicine. However, the “multi-component” and “multi-target” feature of Chinese patent medicine makes it challenge to elucidate the potential therapeutic mechanisms of ZZW on FD. Presently, a novel system pharmacology model including pharmacokinetic parameters, pharmacological data, and component contribution score (CS) is constructed to decipher the potential therapeutic mechanism of ZZW on FD. Finally, 61 components with favorable pharmacokinetic profiles and biological activities were obtained through ADME (absorption, distribution, metabolism, and excretion) screening in silico. The related targets of these components are identified by component targeting process followed by GO analysis and pathway enrichment analysis. And systematic analysis found that through acting on the target related to inflammation, gastrointestinal peristalsis, and mental disorder, ZZW plays a synergistic and complementary effect on FD at the pathway level. Furthermore, the component CS showed that 29 components contributed 90.18% of the total CS values of ZZW for the FD treatment, which suggested that the effective therapeutic effects of ZZW for FD are derived from all active components, not a few components. This study proposes the system pharmacology method and discovers the potent combination therapeutic mechanisms of ZZW for FD. This strategy will provide a reference method for other TCM mechanism research.

功能性消化不良（Functional dyspepsia, FD）是全球范围内高发的胃肠道功能紊乱性疾病，而当前主流治疗方案在西方国家的疗效十分有限。由于该病的临床症状与中医学（Traditional Chinese Medicine, TCM）所称的"痞满"证候相契合，因此可采用中成药枳术丸（Zhi-zhu Wan, ZZW）进行治疗。然而中成药兼具多成分、多靶点的特性，使得阐明枳术丸治疗功能性消化不良的潜在作用机制颇具挑战。本研究构建了一种整合药代动力学参数、药理学数据及成分贡献得分（Component Contribution Score, CS）的新型系统药理学模型，以解析枳术丸治疗功能性消化不良的潜在作用机制。最终通过虚拟（in silico）ADME（吸收、分布、代谢、排泄）筛选，获得了61个具备良好药代动力学特性与生物活性的成分。通过成分靶向预测流程识别出上述成分的相关作用靶点，并进一步开展基因本体（Gene Ontology, GO）富集分析与通路富集分析。系统性分析结果显示，枳术丸可通过作用于与炎症、胃肠道蠕动及精神紊乱相关的靶点，在通路层面实现对功能性消化不良的协同调控与补充干预。此外，成分贡献得分分析显示，29种核心成分的贡献占枳术丸治疗功能性消化不良总得分的90.18%，提示枳术丸的治疗效应并非由少数活性成分主导，而是源于全体活性成分的协同作用。本研究不仅提出了系统药理学研究方法，还揭示了枳术丸治疗功能性消化不良的潜在协同组合式作用机制。该研究策略可为其他中药作用机制研究提供可借鉴的技术范式。