目的 基于肝脏代谢组学探讨白鲜碱药物性肝损伤机制。方法 将SPF级SD雄性大鼠随机分为对照组、给药组（10 mg·kg^-1，相当于成人临床等效剂量的6.17倍，连续给药7 d）及停药（给药7 d后停药7 d）组，计算各组大鼠肝脏指数，HE染色法观察大鼠肝脏组织病理结构；酶联免疫吸附测定（ELISA）法检测血清白细胞介素（IL）-1、IL-6、肿瘤坏死因子（TNF）-α炎症因子水平以及丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）、白蛋白（ALB）水平； UPLC-Q-TOF-MS非靶向代谢组学技术分析各组大鼠肝脏组织代谢谱差异，通过多元统计分析筛选差异代谢标志物，结合京都基因与基因组百科全书（KEGG）通路富集解析核心代谢紊乱机制。结果 给药组大鼠出现明显肝细胞水肿、脂肪变性及炎症浸润；停药7 d后，发现停药组较给药组淋巴细胞浸润减少，肝细胞水肿和肝细胞坏死情况减轻。与对照组相比，给药组大鼠肝脏指数明显上升（P＜0.001）；停药组与给药组相比，肝脏指数有回调趋势（P＜0.001）。与对照组相比，给药组血清肝脏功能指标IL^-1、IL-6、TNF-α、AST、ALT、ALP显著上调（P＜0.01），ALB显著下调（P＜0.05）；与给药组相比，停药组以上指标都有所回调（P＜0.05、0.01）。代谢组学分析筛选出给药组30个、停药组35个差异代谢标志物，涵盖胆汁酸、磷脂、泛酸与辅酶A、嘌呤、脂肪酸等多个代谢类别；差异代谢物富集于泛酸与辅酶A生物合成、嘌呤代谢、初级胆汁酸合成及脂质代谢等通路。结论 白鲜碱致大鼠肝损伤具有可逆性，其核心机制与泛酸与辅酶A生物合成、嘌呤代谢、初级胆汁酸合成及脂质代谢等通路的协同紊乱密切相关。

Objective To explore the mechanism of dictamnine-induced liver injury based on hepatic metabolomics. Methods SPFgrade male SD rats were randomly divided into control, treatment (10 mg·kg^-1, equivalent to 6.17 times the adult clinical equivalent dose, administered continuously for 7 days), and withdrawal groups (treatment for 7 days followed by a 7-day drug-free period). Liver indices were calculated for each group. Histopathological changes in liver tissues were observed using HE staining. Serum levels of inflammatory cytokines including interleukin-1 (IL^-1), IL-6, tumor necrosis factor-alpha (TNF-α), as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) were detected by ELISA. Non-targeted metabolomics analysis using UPLC-Q-TOF-MS was performed to identify differences in liver histopathology and metabolic profiles among groups. Differential metabolites were screened via multivariate statistical analysis, and core metabolic disturbances were analyzed through KEGG pathway enrichment. Results Rats in the treatment group exhibited obvious hepatocyte edema, fatty degeneration, and inflammatory infiltration. After a 7-day withdrawal intervention, the withdrawal group showed reduced lymphocytic infiltration, less hepatocyte edema, and decreased hepatocyte necrosis compared to the treatment group. Compared with the control group, the liver index significantly increased in the treatment group (P<0.001); In contrast, the liver index in the withdrawal group showed a trend toward recovery compared to the treatment group (P<0.001). Compared with the control group, serum liver function indicators including IL^-1, IL-6, TNF-α, AST, ALT, and ALP were significantly upregulated (P<0.01), while ALB was significantly downregulated (P<0.05) in the treatment group; compared with the treatment group, these indicators showed partial recovery in the withdrawal group (P<0.05 or 0.01). Metabolomics analysis identified 31 differential metabolites in the treatment group and 35 in the withdrawal group, covering multiple metabolic categories such as bile acids, phospholipids, pantothenic acid and coenzyme A, purines, and fatty acids. These differentially expressed metabolites were enriched in pathways related to pantothenic acid and coenzyme A biosynthesis, purine metabolism, primary bile acid synthesis, and lipid metabolism. Conclusion Dictamnine -induced liver injury in rats is reversible, and its core mechanism is closely associated with coordinated disturbances in pathways involving pantothenic acid and coenzyme A biosynthesis, purine metabolism, primary bile acid synthesis, and lipid metabolism.

R965

国家重点研发计划“中医药现代化”重点专项2022年度项目（2022YFC3502104-03）；国家重点研发计划“中医药现代化”重点专项2022年度项目（2022YFC3502100）