目的 基于“异类相制”理论，探究淫羊藿Epimedii Folium和女贞子Ligustri Lucidi Fructus对补骨脂Psoraleae Fructus诱导肾阴虚模型大鼠肝损伤的影响及作用机制。方法 以补骨脂诱导的肾阴虚模型大鼠肝损伤为参照，分别给予淫羊藿和女贞子进行干预，通过体质量、肛温、粪便含水量及血清环磷酸腺苷（cyclic adenosine monophosphate，cAMP）/环磷酸鸟苷（cyclic guanosine monophosphate，cGMP）比值评估肾阴虚指征变化情况；通过血清中丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天冬氨酸氨基转移酶（aspartate aminotransferase，AST）活性及肝组织苏木素-伊红（hematoxylin-eosin，HE）染色评估肝脏功能变化；结合代谢组学、关联分析、ROC分析及京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）通路富集分析解析潜在机制。结果 淫羊藿可显著降低模型大鼠体质量和粪便含水量（P＜0.05、0.01），显著升高肛温、cAMP/cGMP比值、ALT及AST活性（P＜0.05、0.001），并加重肝脏炎性细胞浸润，加剧肝损伤；女贞子则可显著逆转上述变化。代谢组学鉴定出17个淫羊藿和女贞子差异调控的共同代谢物，关联分析及ROC分析进一步发现神经酰胺、牛磺胆酸等6个诊断效能良好的差异代谢物，主要涉及亚油酸代谢、鞘脂代谢等8条通路。此外，淫羊藿可显著升高模型大鼠血清中炎性因子白细胞介素-1β（interleukin-1β，IL-1β）、IL-6、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）水平（P＜0.05），并降低抗炎因子IL-10水平；女贞子则逆转上述变化。结论 淫羊藿和女贞子可能通过差异调控肝脏亚油酸代谢等影响炎性细胞因子水平，从而导致补骨脂诱导的肾阴虚模型大鼠肝脏出现毒/效作用差异。为中医“异类相制”理论提供实验依据，并为补骨脂减毒增效研究提供借鉴。

Objective To explore the effect and mechanism of Yinyanghuo (Epimedii Folium) and Nüzhenzi (Ligustri Lucidi Fructus) on Buguzhi (Psoraleae Fructus)-induced liver injury in a rat model of kidney-yin deficiency based on the theory of “heterogeneous medicinals mutual restriction”. Methods The liver injury rats with kidney-yin deficiency model induced by Psoraleae Fructus was taken as a reference, Epimedii Folium and Ligustri Lucidi Fructus were respectively given for intervention, the changes in indicators of kidney-yin deficiency were evaluated by through body weight, anal temperature, fecal water content and cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) ratio in serum. The changes in liver function were evaluated by measuring the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, as well as by staining liver tissue with hematoxylin eosin (HE). Metabolomics, association analysis, ROC analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were combined to elucidate potential mechanisms. Results Epimedii Folium significantly decreased body weight and fecal water content in model rats (P < 0.05, 0.01), significantly increased anal temperature, cAMP/cGMP ratio and activities of ALT, AST (P < 0.05, 0.001), aggravated the infiltration of inflammatory cells in liver and exacerbated liver damage. Ligustri Lucidi Fructus significantly reversed the above changes. Metabolomics identified 17 common metabolites that were differentially regulated between Epimedii Folium and Ligustri Lucidi Fructus. Association analysis and ROC analysis further revealed six differential metabolites with good diagnostic efficacy, including ceramide and taurocholic acid, mainly involving eight pathways such as linoleic acid metabolism and sphingolipid metabolism. In addition, Epimedii Folium could significantly increase the levels of inflammatory factors such as interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) in serum of model rats (P < 0.05), and decrease anti-inflammatory factor IL-10 level. Ligustri Lucidi Fructus reversed the above changes. Conclusion Epimedii Folium and Ligustri Lucidi Fructus may affect the levels of inflammatory cytokines by differentially regulating liver linoleic acid metabolism, leading to differences in toxicity/efficacy in liver of rats with kidney-yin deficiency induced by Psoraleae Fructus. This study provides experimental basis for the theory of “heterogeneous medicinals mutual restriction” in traditional Chinese medicine, and provides reference for the research on reducing toxicity and increasing efficiency of Psoraleae Fructus.

R285.5

国家自然科学基金面上资助项目(82173993,82574685);中原科技创新领军人才项目(254000510038);河南省高校科技创新团队(23IRTSTHN026);河南省医学科技攻关计划项目(SBGJ202403040);河南省卫生健康委员会国家中医药传承创新中心联合共建科研专项(2024ZXZX1179)