目的 在“心主神明”理论指导下，基于网络药理学、分子对接及分子动力学模拟，揭示开心散治疗认知障碍与抑郁症“异病同治”的共同作用机制，为经典理论提供现代科学诠释。方法 通过中药系统药理学数据库与分析平台（TCMSP）、中医药生物信息学数据库（ETCM）筛选开心散活性成分[口服利用度（OB）≥ 30%，类药性（DL）≥ 0.18]，运用SwissTargetPrediction预测成分靶点；从GeneCards、OMIM获取认知障碍与抑郁症疾病靶点；取交集后构建蛋白质-蛋白质相互作用（PPI）网络，通过CytoNCA筛选核心靶点；利用Metascape进行基因本体（GO）注释及京都基因与基因组百科全书（KEGG）通路富集分析；构建药物-成分-靶点-通路-疾病网络。采用AutoDock Vina进行分子对接（含再对接验证），对优选复合物进行100 ns分子动力学模拟，评估结合稳定性。结果 共筛选出52个活性成分，对应288个靶点，与疾病交集获得115个共同靶点，进一步筛选出11个核心靶点[肿瘤坏死因子（TNF）、蛋白激酶B（AKT1）、表皮生长因子受体（EGFR）、前列腺素内过氧化物合酶2（PTGS2）、信号转导和转录激活因子3（STAT3）、基质金属蛋白酶-9（MMP9）等]。KEGG富集显示核心靶点显著富集于环磷酸腺苷（cAMP）信号通路、磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）信号通路、5-羟色胺（5-HT）能突触、钙信号通路等。分子对接证实茯苓酸与PTGS2（-44.3 kJ·mol^-1）、猪苓酸C与过氧化物酶体增殖物激活受体γ（PPARG）（-40.7 kJ·mol^-1）、山柰酚与MMP9（-39.9 kJ·mol^-1）、人参皂苷Rh₄与MMP9（-38.5 kJ·mol^-1）等具有良好结合活性。分子动力学模拟显示人参皂苷Rh₄-MMP9复合物在100 ns内稳定[均方根偏差（RMSD） 0.5～1.6 nm，Rg 1.6～2.2 nm]，吉布斯自由能景观呈现单一能量漏斗。结论 开心散通过多成分、多靶点、多通路协同调控“心-脑-神”轴，实现认知障碍与抑郁症的异病同治。其机制可归纳为3个维度： ①益心气、养脑窍（激活cAMP/PI3K-Akt/EGFR通路，增强心肌收缩力、改善脑灌注）； ②祛痰浊、清神府[抑制PTGS2/核因子-κB（NF-κB）/MMP9通路，减轻神经炎症、保护血脑屏障]；③调气血、安神明（调节5-HT能突触/钙信号通路，恢复神经递质平衡与突触可塑性）。

Objective Guided by the theory of “Heart Governing Shenming”, this study aims to elucidate the common mechanism of Kaixin Powder in treating cognitive impairment and depression (“treating different diseases with the same therapy”) using network pharmacology, molecular docking, and molecular dynamics simulation, thereby providing a modern scientific interpretation for this classic theory. Methods Active components of Kaixin Powder were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Encyclopedia of Traditional Chinese Medicine (ETCM) databases [oral bioavailability (OB) ≥ 30%, drug-likeness (DL) ≥ 0.18]. Component targets were predicted using SwissTargetPrediction. Disease targets for cognitive impairment and depression were obtained from GeneCards and OMIM. After intersecting the targets, a PPI network was constructed and core targets were screened using CytoNCA. GO and KEGG enrichment analyses were performed using Metascape, and a drug-component-target-pathway-disease network was constructed. Molecular docking was performed using AutoDock Vina (including re-docking validation), and 100 ns molecular dynamics simulations were conducted for the selected complex to evaluate binding stability. Results A total of 52 active components and 288 corresponding targets were identified. Intersection with disease targets yielded 115 common targets, from which 11 core targets (TNF, AKT1, EGFR, PTGS2, STAT3, MMP9, etc.) were further screened. KEGG enrichment showed that the core targets were significantly enriched in the cAMP signaling pathway, PI3K-Akt signaling pathway, serotonergic synapse, calcium signaling pathway, etc. Molecular docking confirmed good binding affinities, including pachymic acid with PTGS2 (-44.3 kJ·mol^-1), polyporenic acid C with PPARG (-40.7 kJ·mol^-1), kaempferol with MMP9 (-39.9 kJ·mol^-1), and ginsenoside Rh₄ with MMP9 (-38.5 kJ·mol^-1). Molecular dynamics simulations demonstrated that the ginsenoside Rh₄-MMP9 complex remained stable within 100 ns (RMSD 0.5-1.6 nm, Rg 1.6-2.2 nm), and the Gibbs free energy landscape exhibited a single energy funnel. Conclusion Kaixin Powder exerts its effect of treating cognitive impairment and depression (“treating different diseases with the same therapy”) by synergistically regulating the “Heart-Brain-Shen” axis through multiple components, multiple targets, and multiple pathways. Its mechanism can be summarized into three dimensions: ①benefiting heart qi and nourishing brain orifices (activating cAMP/PI3K-Akt/EGFR pathways to enhance myocardial contractility and improve cerebral perfusion);②eliminating phlegm turbidity and clearing the spirit palace (inhibiting PTGS2/NF-κB/MMP9 pathways to alleviate neuroinflammation and protect the blood-brain barrier);③regulating qi and blood to calm the shen (modulating serotonergic synapse/calcium signaling pathways to restore neurotransmitter balance and synaptic plasticity).

R285.5

国家重点研发课题（2022YFC3501103）；中医药传承创新科研专项（2024ZXZX1012）