Nawaka N.Lertcanawanichakul M.Porntadavity S.Pussadhamma B.Jeenduang N.Mahidol University2025-05-132025-05-132025-12-01Scientific Reports Vol.15 No.1 (2025)https://repository.li.mahidol.ac.th/handle/20.500.14594/110084Kratom (Mitragyna speciosa (Korth.) Havil.) has been reported to reduce serum lipids. However, the molecular mechanism underlying hypolipidaemic effect of kratom is still unclear. This study aimed to investigate the effects of kratom leaf extracts on hypolipidaemia via the expression of LDLR and PCSK9 in HepG2 cells. Real-time RT-PCR, Western blotting, and flow cytometry analyses revealed that kratom leaf extracts from red-vein and white-vein strains increased LDLR protein expression but decreased that of PCSK9 via downregulation of SREBP-2 and HNF-1α. Furthermore, a confocal laser scanning microscope revealed that kratom leaf extracts from both strains increased LDL uptake into HepG2 cells. The bioactive compounds, e.g., mitragynine, quercetin, and rutin, in kratom leaf extracts from both strains were characterized by LC-MS/MS analysis. Mitragynine also significantly increased LDLR protein expression but decreased that of PCSK9. Molecular docking studies demonstrated that mitragynine had the strongest binding affinity for EGF-A domain of LDLR (– 7.57 kcal/mol), whereas quercetin had the strongest binding affinity for PCSK9 (– 8.45 kcal/mol). In conclusion, kratom leaf extracts from red-vein and white-vein strains possessed hypolipidaemic effects by decreased PCSK9 expression and increased LDLR expression through the modulation of SREBP2 and HNF-1α. Therefore, kratom could serve as a potential supplement for ameliorating hypercholesterolemia.MultidisciplinaryArticleSCOPUS10.1038/s41598-025-00711-12-s2.0-10500428213120452322