Lipid-lowering mechanism of Swietenia macrophylla King leaves through SREBP-1c/FASN axis and RNA sequencing validation

Swietenia macrophylla King, a medicine food homology, has garnered attention for the hypoglycemic and hypolipidemic activities of its fruit in the improvement of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the glucolipid regulating properties of its leaf remains unexplored. The study sought to examine the pharmacological mechanisms underlying the lipid-lowering effects of Swietenia macrophylla King leaf extract (SLE) and its active constituent senegalension B (one of 31 limonoids in SLE). Glucolipid regulation by SLE and active constituent was evaluated through cellular triglyceride content and peripheral glucose levels in primary mouse hepatocytes (PMHs), SLE dose-dependently reduced lipid accumulation in the range of 23.65±3.41% to 37.39±2.50%, validated by Oil Red O staining. Network pharmacology and RNA sequencing identified SREBP-1c/FASN axis as the key mechanism by which SLE improved lipid accumulation in PMHs, consistent with senegalension B. RT-qPCR and Western blot showed that SLE (40 μg/mL) decreased the lipid synthesis regulator SREBP-1c mRNA and protein levels by 60.69±1.69% and 48.07±11.83%, respectively, whereas senegalension B (40 μM) achieved 55.42 ±2.29% and 34.34±8.49% inhibition. Dual-luciferase reporter assays revealed that senegalension B suppressed SREBP-1c promoter activity in Hep G2 cells. Molecular docking suggested a potential interaction with SREBP1, consistent with molecular dynamics simulation comparing binding affinity and stability with LXRα, indicating that senegalension B may exert lipid-lowering activity by targeting key proteins involved in lipid synthesis, such as SREBP-1c. This study elucidated the mechanisms and potential of SLE and senegalension B in regulating MASLD through in vitro investigation, expanded the utilization of Swietenia macrophylla King resources, and provided a candidate plant-derived compound for dietary therapy.