Integrating metabolomics and network pharmacology analysis provides new insights into the lipid metabolism disorder of Abrus mollis.

Abrus mollis Hance (AM), a traditional medicinal used for hepatoprotection in the south of China, has demonstrated potential in ameliorating lipid metabolism disorders (LMD). However, the underlying mechanisms remain elusive. To explore the mechanisms by which AM regulates lipid metabolism in mice on a high-fat diet through integrated metabolomics and network pharmacology. An HFD-induced dyslipidemia mice model was established to evaluate the therapeutic effectiveness of AM. Untargeted metabolomics identified hepatic endogenous metabolites and associated pathways. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) characterized bioactive compounds and blood-absorbed components in AM. Network pharmacology analysis of blood-absorbed components, combined with molecular docking, predicted potential active constituents targeting lipid metabolism disorders, identified critical targets, and mapped metabolic pathways. Core regulatory mechanisms were elucidated through integrative analysis of network pharmacology predictions and metabolomics data. Transcriptional levels and protein expression of related genes were analyzed in murine hepatic tissues using real-time quantitative PCR (RT-qPCR) and Western blotting. Animal experiments had confirmed the efficacy of AM in alleviating lipid abnormalities induced by HFD. Twenty-one hepatic endogenous metabolites were identified, with major pathways encompassing arachidonic acid metabolism, linoleic acid metabolism, among others. UPLC-Q-TOF/MS analysis characterized 50 bioactive compounds in AM, 24 of which were detected in plasma. Network pharmacology prioritized schaftoside, hyperoside, protocatechuic acid, and vitexin as core components targeting TP53, SRC, ESR1, and PIK3CA, while molecular docking validated their strong binding affinities. KEGG analyses indicated that the PI3K-Akt signaling pathway acts as the core regulatory pathway which was further confirmed by integrated of metabolomics and network pharmacology analyses. Subsequent RT-qPCR and WB further evidenced AM-mediated downregulation of PI3K/Akt pathways-associated transcription factors and proteins. This study elucidated the multi-target mechanisms of AM via the PI3K/Akt signaling pathway and highlighted its therapeutic potential in modulating lipid metabolism disorders.