Combination of Plasma Pharmacochemistry, RNA-Seq, and Molecular Docking Strategies to Reveal the Mechanism of the Alkaloid Fraction of Nelumbinis folium for the Treatment of Hyperlipidemia.

Nelumbinis folium (N. folium) exhibits hypolipidemic effects and shows great potential for application in lipid-lowering drugs and healthcare products. This study aimed to investigate the mechanism underlying the hypolipidemic effects of the alkaloid fraction of N. folium (AFN). Animal experiments demonstrated that AFN significantly reduced blood lipid levels and ameliorated liver damage in hyperlipidemic mice. RNA-seq analysis identified 26 reverse-regulated differentially expressed genes (DEGs), which were primarily involved in the PPAR signaling pathway, fat digestion and absorption, and fatty acid degradation. Using UPLC-MSn, 30 plasma-absorbed components were identified, including 13 prototype alkaloids. Among these, three key active components-nuciferine, N-nornuciferine, and N-methylisococlaurine-were screened via network topology analysis. Molecular docking revealed strong binding affinities between these compounds and key targets. The results showed that N-methylisococlaurine bound to SLC27A4 and CPT1A with strong affinity, while nuciferine and N-nornuciferine bound to ACADVL and PPARA. RT-qPCR results confirmed that AFN modulates the expression of FABP1, SLC27A4, PPARA, CPT1A, ACAA2, APOC3, and APOA4. These findings suggest that AFN exerts its hypolipidemic effects through multi-component, multi-target, and multi-pathway mechanisms.