基于整合代谢组学和网络药理学的研究：四妙勇安汤在调节鞘脂代谢及改善血栓闭塞性脉管炎血管损伤中的作用

《Journal of Ethnopharmacology》：Integrated metabolomics and network pharmacology study on Si-miao-yong-an Decoction in regulating sphingolipid metabolism and improving vascular injury on thromboangiitis obliterans

中药复方 FYHX 通过抑制背根神经节 chemokine 信号通路和脊髓 IL-17 信号通路缓解 CFA 模型诱导的慢性疼痛，并鉴定 42 种活性成分和小分子化合物。

　　
Fuyuan Huoxue Decoction (FYHX) is a traditional Chinese medicine formulation with historical roots in classical medical texts such as Yixue Faming. The decoction comprises eight herbs in specific ratios, traditionally used for treating traumatic injuries and blood stasis-related pain syndromes. Recent clinical applications have extended its use to soft tissue injuries, neuropathic pain, and chondritis, but the underlying bioactive components and mechanisms remain unclear. This study systematically investigates FYHX's analgesic effects through a comprehensive approach involving pharmacological modeling, omics technologies, and molecular validation.

The research employs a CFA-induced chronic pain rat model to simulate clinical conditions. By measuring mechanical and thermal pain thresholds before and after treatment, the study demonstrates that FYHX significantly reduces hyperalgesia at multiple time points, particularly after 21 days of administration. This aligns with traditional clinical observations where prolonged medication effects are characteristic of herbal formulations.

Key findings reveal FYHX's dual action on pain signaling pathways. In the dorsal root ganglia (DRG), the chemokine signaling pathway is identified as a primary target through expression profile analysis and molecular docking simulations. This pathway regulates immune cell trafficking and neuroinflammation, with downregulation of CCR7 and other chemokine-related proteins observed. Simultaneously, in the spinal cord, the IL-17 signaling axis is activated, contributing to chronic pain maintenance. The study confirms that FYHX treatment leads to suppression of IL-17A and IL-17RA expression levels in spinal cord tissue.

The chemical analysis component is particularly noteworthy. High-performance liquid chromatography-mass spectrometry (HPLC-MS) identifies 42 bioactive molecules and metabolites in FYHX. Among these, four compounds - Scutellarein, 3,4'-Dibydroxyflavone, 5,6,7-Trimethoxyflavone, and Armillarisin A - demonstrate significant independent analgesic effects when administered at specific doses. This dual approach of systemic component identification and targeted compound validation provides a robust framework for translating herbal medicine into modern pharmacological research.

The methodology integration deserves emphasis. Network pharmacology models link herbal components to biological targets, while transcriptomic analysis provides temporal insights into pathway activation. Molecular docking further confirms the structural basis of target interactions. The complementary approaches effectively bridge the gap between traditional efficacy and scientific validation.

Clinical implications are substantial. The identified mechanisms align with current understanding of chronic pain pathophysiology, particularly the role of IL-17 in autoimmune and inflammatory pain conditions. The dual regulation of DRG and spinal cord pathways explains the comprehensive pain relief observed. This provides a theoretical basis for repurposing FYHX in treating postherpetic neuralgia, diabetic neuropathy, and other chronic inflammatory pain conditions.

Limitations include the reliance on animal models and the metabolic fate of herbal components during administration. The study also doesn't explore long-term effects or dose-response relationships beyond 21 days. Future research should focus on human trials, mechanistic validation through single-cell RNA sequencing, and pharmacokinetic studies to optimize therapeutic dosing.

The research contributes to three important areas: first, it validates the traditional application of FYHX through modern analytical methods; second, it provides a blueprint for dissecting multi-component中药 formulations using integrative omics technologies; third, it identifies specific active compounds that can be further developed into isolated pharmaceuticals. The four identified key compounds show comparable efficacy to whole decoction, suggesting potential for developing more efficient derivatives.

This study advances the scientific understanding of herbal medicine by demonstrating that FYHX's analgesic effects are mediated through specific biological pathways rather than nonspecific anti-inflammatory actions. The identified targets (IL-17A/IL-17RA, CCR7, MMP-9) are potential therapeutic biomarkers. The methodology established here can serve as a template for similar investigations into other TCM formulations.

The practical applications include both direct clinical use and drug development. For acute traumatic injuries, FYHX demonstrates rapid pain relief through enhanced blood circulation and reduced inflammation. For chronic pain management, the identified pathways offer targets for developing new combination therapies or monotherapy agents. The four bioactive compounds identified could be candidates for further structural optimization and clinical trials.

The study's findings have significant implications for integrative medicine. By combining network pharmacology predictions with experimental validations, it demonstrates the feasibility of translating herbal formulas into evidence-based pharmacotherapy. This approach bridges the gap between traditional medicine practices and modern scientific validation requirements.

In summary, this research provides a comprehensive analysis of FYHX's analgesic mechanisms through state-of-the-art technologies. It not only validates traditional clinical applications but also opens new avenues for drug development from traditional Chinese medicine. The identified key compounds and pathways offer valuable targets for future research in chronic pain management, particularly for conditions where current treatments have limitations. This work exemplifies the potential of systems pharmacology approaches in elucidating the efficacy of complex herbal formulations.