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.

heterogeneous medicinals mutual restriction  /  Psoraleae Fructus  /  liver injury  /  Epimedii Folium  /  Ligustri Lucidi Fructus  /  metabolomics  /  ceramide  /  taurocholic acid  /  phosphatidylinositol  /  7-dehydrocholesterol  /  β-D-glucuronoside  /  linoleic acid