目的 采用网络药理学与分子对接技术探讨郁金四逆散治疗青少期抑郁症的作用机制，并进行动物实验 验证。方法 （1）采用中药系统药理学数据库与分析平台（TCMSP）、中医药百科全书数据库（ETCM）、 BATMAN-TCM 数据库筛选郁金四逆散的有效成分与作用靶点，GeneCards 数据库筛选与青少期抑郁症相关的 疾病靶点，取二者交集获得郁金四逆散治疗青少期抑郁症的潜在作用靶点。利用 STRING 数据库、Cytoscape 3.7.2 软件构建“复方-活性成分-作用靶点”网络及蛋白质-蛋白质互作（PPI）网络，并筛选出郁金四逆散治疗 青少期抑郁症的关键有效成分及核心靶点。借助 OmicShare 平台对交集靶点进行 GO 功能与 KEGG 通路富集分 析，并采用 CB-Dock 平台对关键有效成分与核心靶点进行分子对接。（2）采用母婴分离结合慢性不可预测性应 激复制青少期抑郁小鼠模型。将 48 只刚出生的 C57BL/6J 小鼠随机分为空白组、模型组、氟西汀组（5 mg·kg-1 ）及 郁金四逆散低（6.1 g·kg-1 ）、中（12.2 g·kg-1 ）、高（24.4 g·kg-1 ）剂量组，每组 8 只。空白组、模型组小鼠灌胃生理 盐水，各给药组灌胃相应浓度的药物，连续干预 27 d。采用一系列行为学实验（旷场实验、高架十字迷宫实 验、蔗糖偏好实验、悬尾实验、强迫游泳实验）检测小鼠的焦虑、抑郁样行为变化；采用尼氏染色、HE 染色 观察小鼠海马组织病理变化；Western Blot 法检测小鼠海马组织中突触后致密蛋白 95（PSD-95）、突触素 （SYN）、生长相关蛋白 43（GAP-43）、促分裂原活化蛋白激酶 1/2（MEK1/2）、细胞外信号调节激酶 1/2（ERK1/2） 及磷酸化 MEK1/2（p-MEK1/2）、磷酸化 ERK1/2（p-ERK1/2）的蛋白表达水平。结果 （1）网络药理学结果筛选 出郁金四逆散抗青少期抑郁症的关键有效成分有姜黄素、槲皮素、山柰酚、柚皮素等，核心靶点有 TP53、 STAT3、AKT1、SRC、ESR1、JUN、EGFR、EP300、MAPK1、MAPK3 等。郁金四逆散治疗青少期抑郁症涉及 突触、信号受体结合、对有机物质的响应等过程，治疗机制与 MAPK 信号通路、PI3K-Akt 信号通路等有关。 分子对接结果显示，郁金四逆散的关键有效成分与核心靶点结合活性良好。（2）与空白组比较，模型组小鼠的中 央停留时间、开臂停留时间比减少（P＜0.01），蔗糖偏好率降低（P＜0.01），强迫游泳以及悬尾实验中的不动时 间显著延长（P＜0.01）。与模型组比较，氟西汀组、郁金四逆散中剂量组小鼠的中央停留时间及郁金四逆散低、 中剂量组小鼠的开臂停留时间比增加（P＜0.01）；氟西汀组及郁金四逆散低、中、高剂量组小鼠的蔗糖偏好率 显著增加（P＜0.01），悬尾实验以及强迫游泳实验中的不动时间显著缩短（P＜0.01）。（3）与空白组比较，模型组 小鼠海马 CA1、CA3、DG 区锥体细胞层变薄、细胞稀疏、细胞排列紊乱，部分区域可见胞核固缩、空泡样变， 部分细胞的尼氏体颗粒模糊、减少。与模型组比较，各给药组小鼠神经元数量增加，细胞密度、排列均明显恢 复正常，尼氏体状态改善。（4）与空白组比较，模型组小鼠海马 PSD-95、SYN、GAP-43、p-MEK1/2/MEK1/2、 p-ERK1/2/ERK1/2 蛋白表达水平均显著降低（P＜0.01）。与模型组比较，氟西汀组及郁金四逆散中剂量组小鼠 海马组织 PSD-95、SYN、GAP-43、p-MEK1/2/MEK1/2、p-ERK1/2/ERK1/2 蛋白表达水平显著升高（P＜0.05， P＜0.01）；郁金四逆散高剂量组小鼠海马组织 PSD-95、p-ERK1/2/ERK1/2 及郁金四逆散低剂量组 GAP-43 蛋白表达水平显著升高（P＜0.05），郁金四逆散低剂量组小鼠海马组织 PSD-95、SYN、p-MEK1/2/MEK1/2、pERK1/2/ERK1/2 蛋白表达及郁金四逆散高剂量组 SYN、GAP-43、p-MEK1/2/MEK1/2 蛋白表达有升高趋势，但 差异无统计学意义（P＞0.05）。结论 郁金四逆散防治青少期抑郁症具有多靶点、多通路的作用特点，其作用机 制可能通过调节 MAPK/ERK 信号通路，改善抑郁小鼠海马组织突触可塑性，从而发挥抗青少期抑郁症的作用。

Objective To investigate the mechanism of Yujin Sini San in the treatment of adolescent depression using network pharmacology and molecular docking， and to validate the findings through animal experiments. Methods （1） Active components and potential targets of Yujin Sini San were identified using the TCMSP， ETCM， and BATMAN-TCM databases. Disease targets related to adolescent depression were retrieved from the GeneCards database. Intersection targets were obtained as potential therapeutic targets. A “compound-active component-target” network and a protein-protein interaction （PPI） network were constructed using the STRING database and Cytoscape 3.7.2 software to screen key active components and core targets. GO functional and KEGG pathway enrichment analyses of the intersection targets were performed via the OmicShare platform. Molecular docking between key components and core targets was conducted using the CB-Dock platform.（2） An adolescent depression mouse model was established using maternal separation combined with chronic unpredictable stress. Forty-eight newborn C57BL/6J mice were randomly divided into six groups （n=8）：a control group，a model group，a fluoxetine group （5 mg·kg⁻¹），and low-dose （6.1 g·kg-1 ）， medium-dose （12.2 g·kg⁻¹），and high-dose （24.4 g·kg⁻¹） of Yujin Sini San groups. The control and model groups received saline， while the treatment groups received corresponding drugs via gavage for 27 consecutive days. A series of behavioral tests （open field，elevated plus maze，sucrose preference，tail suspension，and forced swimming tests） were conducted to assess anxiety-like and depression-like behaviors. Pathological changes in the hippocampus were observed using Nissl and HE staining. Western Blot was used to measure protein expression levels of postsynaptic density protein 95（PSD-95），synaptophysin （SYN），growth-associated protein 43（GAP-43），mitogen-activated protein kinase 1/2（MEK1/2），extracellular signal-regulated kinase 1/2（ERK1/2），phosphorylated MEK1/2（p-MEK1/2）， and phosphorylated ERK1/2 （p-ERK1/2） in hippocampal tissue. Results （1） Network pharmacology identified curcumin， quercetin， kaempferol， and naringenin as key active components of Yujin Sini San against adolescent depression， with TP53， STAT3， AKT1， SRC， ESR1， JUN， EGFR， EP300， MAPK1， and MAPK3 as core targets. The therapeutic effects involved processes such as synapse organization，signal receptor binding，and response to organic substances，primarily through the MAPK and PI3K-Akt signaling pathways. Molecular docking confirmed favorable binding activity between the key components and core targets.（2） Compared with the control group，model mice exhibited significantly reduced central zone time and open-arm time rate （P＜0.01）， decreased sucrose preference rate （P＜0.01），and significantly prolonged immobility time in the forced swimming and tail suspension tests （P＜0.01）. Compared with the model group，the fluoxetine and medium-dose Yujin Sini San groups showed increased central zone time，while the low- and medium-dose Yujin Sini San groups showed increased open-arm time rate （P＜ 0.01）. All treatment groups exhibited significantly increased sucrose preference rate （P＜0.01） and significantly reduced immobility time in the tail suspension and forced swimming tests （P＜0.01）.（3）Compared with controls，the model group displayed hippocampal pathological changes in CA1，CA3 and DG regions，including thinning pyramidal cell layers，sparse cell distribution，disorganized arrangement，nuclear pyknosis，vacuolation，and reduced/diffuse Nissl bodies. All treatment groups showed increased neuron count， improved cell density and arrangement， and ameliorated Nissl body status.（4）Model mice exhibited significantly lower protein expression levels of hippocampal PSD-95，SYN，GAP-43，p-MEK1/2/MEK1/2，and p-ERK1/2/ERK1/2 compared to controls （P＜0.01）. Compared with the model group，the fluoxetine and medium-dose Yujin Sini San groups showed significantly elevated expression of these proteins （P＜0.05，P＜0.01）. The high-dose group showed significantly increased PSD-95 and p-ERK1/2/ ERK1/2 expression， and the low-dose group showed significantly increased GAP-43 protein expression （P＜0.05）. Although trends of increase were observed for PSD-95，SYN，p-MEK1/2/MEK1/2，p-ERK1/2/ERK1/2 in the lowdose group and for SYN，GAP-43，p-MEK1/2/MEK1/2 in the high-dose group，the differences were not statistically significant （P＞0.05）. Conclusion Yujin Sini San exerts preventive and therapeutic effects against adolescent depression through multiple targets and pathways. Its mechanism is potentially associated with regulating the MAPK/ ERK signaling pathway and improving synaptic plasticity in the hippocampus of depressed mice.

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国家自然科学基金项目（82274443）；广西自然科学基金重点项目（2023GXNSFDA026027）；广西重点研发计划项目（桂科 AB23026137）；广东省普通高校重点领域专项（2024ZDZX2039）。