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ETHNOPHARMACOLOGICAL RELEVANCE Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: We aimed to screen the effective constituent of N. nucifera alkaloids and elucidated the potential mechanism for treating hyperlipidemia. A triple combination strategy of UHPLC-MSn, hypolipidemic activity and transcriptome sequencing was built to unveil the hypolipidemic mechanism of Nelumbo nucifera alkaloid. MATERIALS AND METHODS We comprehensively investigated the characterization of N. nucifera alkaloids by using UHPLC-LTQ-Orbitrap MSn. And the hypolipidemic activity of candidate active ingredients were evaluated on sodium oleate-induced HepG2 cell. Finally, O-nornuciferine and N. nucifera alkaloid extraction were analyzed by RNA sequence (RNA-seq) to decipher the underlying hypolipidemic mechanism and were verified by qRT-PCR. RESULTS 35 compounds were identified from N. nucifera alkaloid extraction by UHPLC-LTQ-Orbitrap MSn. Among them, O-nornuciferine and N. nucifera alkaloid extraction which showed significant hypolipidemic activity were analyzed by transcriptome sequencing. After the intervention of O-nornuciferine and N. nucifera alkaloid extraction, 1 and 158 differentially expressed genes (DEGs) were identified, severally. The enrichment analysis indicated that the hypolipidemic effect was adjusted by the expression of numerous key DEGs involved in bile secretion, glycerolipid and sphingolipid metabolism, PPAR signaling pathway. CONCLUSIONS O-nornuciferine and N. nucifera alkaloids had exibited significant effects in hyperlipidemia. The candidate genes were LDLR, LPL and ANGPTL4, etc. It was most likely that they adjusted lipid metabolism by modulating expression levels of various key factors which were involved in bile secretion, glycerolipid metabolism, sphingolipid metabolism and PPAR signaling pathway, and so on. This study clarified the hypolipidemic mechanism of the alkaloids in N. nucifera, and laid a foundation for the subsequent development of clinical application and better quality of N. nucifera.