目的 基于网络药理学及动物实验探讨粉防己碱治疗重症急性胰腺炎（SAP）的分子机制。方法 （1）采 用 Swiss Target Prediction、BATMAN-TCM 数据库检索获得粉防己碱作用靶点，采用 GeneCards、OMIM、 DisGeNet、PharmGkb 数据库检索获得 SAP 疾病靶点，对二者取交集并绘制韦恩图，得到粉防己碱治疗 SAP 的 潜在作用靶点（共同靶点）。通过 String 数据库构建潜在作用靶点蛋白互作（PPI）网络，筛选关键靶点。利用 David、KOBAS 数据库对潜在作用靶点进行 GO 功能及 KEGG 通路富集分析。（2）将昆明小鼠随机分为空白对照 组、模型组、粉防己碱组，每组 10 只。模型组及粉防己碱组小鼠均给予腹腔注射 20% L-精氨酸（3.5 g·kg-1 ）， 共 2 次，每次间隔 1 h，复制 SAP 小鼠模型。于末次注射 L-精氨酸 4 h 后，粉防己碱组给予粉防己碱溶液 （120 mg·kg-1 ）腹腔注射，每天 2 次，连续 3 d。计算胰腺脏体比；采用全自动生化分析仪检测血清淀粉酶水平； HE 染色法观察胰腺组织病理变化，并从组织水肿、炎症及坏死三个方面进行评分；免疫组化法观察胰腺组织 IL-6、p-STAT3 表达情况；Western Blot 法检测胰腺组织 IL-6、p-STAT3、STAT3 蛋白表达水平。结果 （1）共 分析得到粉防己碱治疗 SAP 的潜在作用靶点 24 个， AKT1、ERBB2、SRC、MTOR、PIK3CA、CXCR4、JAK2 等为关键靶点；GO 功能分析的生物过程主要涉及蛋白质自身磷酸化、肽基-酪氨酸磷酸化、蛋白磷酸化、凋 亡过程的负调控；KEGG 通路主要涉及 PI3K-Akt 信号通路、JAK-STAT 信号通路、TLR 信号通路、Rap1 信号 通路、FoxO 信号通路等。（2）与空白对照组比较，模型组小鼠胰腺结构明显破坏，出现大量腺泡细胞变性坏死， 仅残存少量分散的腺泡细胞，间质高度水肿，伴大量炎性细胞浸润；胰腺组织水肿评分、炎症评分、坏死评 分、总体评分、胰腺脏体比相对值及血清淀粉酶水平均显著升高（P＜0.01）；小鼠胰腺间质可见大量 IL-6、 p-STAT3 阳性表达，IL-6、p-STAT3/STAT3 蛋白表达水平均显著升高（P＜0.01）。与模型组比较，粉防己碱组 小鼠胰腺结构损伤程度明显减轻，腺泡细胞坏死范围明显缩小，间质水肿程度减轻，仅见少量炎症细胞浸润； 胰腺组织水肿评分、炎症评分、坏死评分、总体评分、胰腺脏体比相对值及血清淀粉酶水平均显著降低（P＜ 0.01）；小鼠胰腺间质的 IL-6、p-STAT3 阳性表达明显减少，IL-6、p-STAT3/STAT3 蛋白表达水平均显著降低 （P＜0.01）。结论 粉防己碱防治 SAP 具有多靶点、多通路的作用特点，可能通过抑制 IL-6/STAT3 信号通路改 善 SAP 小鼠胰腺组织的炎症反应。

Objective To investigate the molecular mechanism of tetrandrine in the treatment of severe acute pancreatitis （SAP） based on network pharmacology and animal experiments. Methods （1） The targets of tetrandrine were obtained by Swiss Target Prediction and BATMAN-TCM data retrieval，and the disease targets of SAP were obtained by GeneCards，OMIM，DisGeNet and PharmGkb database retrieval. The intersection of the two was drawn and the Venn diagram was drawn to obtain the potential targets of tetrandrine in the treatment of SAP （common targets）. The potential target protein-protein interaction （PPI） network was constructed by String database to screen key targets. GO function and KEGG pathway enrichment analysis of potential targets were performed using David and KOBAS databases. （2） Kunming mice were randomly divided into blank control group，model group and tetrandrine group，with 10 mice in each group. The mice in the model group and the tetrandrine group were given intraperitoneal injection of 20% L-arginine （3.5 g·kg-1 ） twice at an interval of 1 hour to replicate the SAP mouse model. At 4 hours after the last injection of L-arginine，the tetrandrine group was given intraperitoneal injection of tetrandrine solution （120 mg·kg-1 ）， twice a day for 3 consecutive days. The ratio of pancreas to body was calculated；serum amylase level was detected by automatic biochemical analyzer；HE staining was used to observe the pathological changes of pancreatic tissue，and the scores were scored from three aspects ： tissue edema ， inflammation and necrosis. The expressions of IL-6 and p-STAT3 in pancreatic tissue was observed by immunohistochemistry. The protein expression levels of IL-6，p-STAT3 and STAT3 in pancreatic tissue were detected by Western Blot. Results （1） A total of 24 potential targets of tetrandrine in the treatment of SAP were obtained，AKT1，ERBB2，SRC，MTOR，PIK3CA，CXCR4 and JAK2 were the key targets. The biological process of GO functional analysis mainly involves the negative regulation of protein autophosphorylation，peptide-tyrosine phosphorylation，protein phosphorylation and apoptosis. KEGG pathway mainly involves PI3K-Akt，JAK-STAT，TLR Rap1 and FoxO signaling pathways，etc.（2）Compared with the blank control group，the pancreatic structure of the mice in the model group was significantly damaged，with a large number of acinar cells degeneration and necrosis，only a small number of dispersed acinar cells，high interstitial edema，and a large number of inflammatory cell infiltration. The pancreatic tissue edema score， inflammation score， necrosis score， overall score，relative value of pancreatic body ratio and serum amylase level were significantly increased （P＜0.01）. A large number of IL-6 and p-STAT3 positive expressions were observed in the pancreatic interstitium of mice，and the protein expression levels of IL-6 and p-STAT3/STAT3 were significantly increased （P＜0.01）. Compared with the model group，the degree of pancreatic structural damage in the tetrandrine group was significantly reduced，the scope of acinar cell necrosis was significantly reduced，the degree of interstitial edema was reduced，and only a small amount of inflammatory cell infiltration was observed. The pancreatic tissue edema score，inflammation score，necrosis score， overall score，relative value of pancreatic body ratio and serum amylase level were significantly decreased （P＜0.01）. The positive expressions of IL-6 and p-STAT3 in pancreatic interstitium of mice was significantly decreased，and the protein expression levels of IL-6 and p-STAT3/STAT3 were significantly decreased （P＜0.01）. Conclusion Tetrandrine has the characteristics of multi-target and multi-pathway in the prevention and treatment of SAP，which may improve the inflammatory response of pancreatic tissue in SAP mice by inhibiting IL-6/STAT3 signaling pathway.

R285.5

国家自然科学基金项目（81603420）；陕西省科技厅重点研发计划项目（2023-YBSF-363）；陕西省中医体质与疾病防治重点实验室开放 课题（KF202309）；陕西中医药大学大学生创新创业训练计划项目（S202210716100）。